# Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia

Félicie Lorenc, Luc Dupuis, Raphaelle Cassel

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Félicie Lorenc, Luc Dupuis, Raphaelle Cassel. Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia. Neurobiology of Disease, 2024, 203, pp.106748. 10.1016/j.nbd.2024.106748. inserm-05508962

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Review

# Impairments of inhibitory neurons in amyotrophic lateral sclerosis and frontotemporal dementia

Félicie Lorenc, Luc Dupuis, Raphaelle Cassel*

Université de Strasbourg, INSERM, UMR-S 1329, Strasbourg Translational Neuroscience and Psychiatry, CRBS, Strasbourg, France

<figure><img src="image_3.png" /></figure>

## ARTICLE INFO

### Keywords

- Amyotrophic lateral sclerosis
- Frontotemporal dementia
- Inhibition
- Inhibitory neurons
- Interneurons
- GABA
- Glycine

## ABSTRACT

Amyotrophic lateral sclerosis and frontotemporal dementia are two fatal neurodegenerative disorders. They are part of a pathophysiological continuum, displaying clinical, neuropathological, and genetic overlaps. There is compelling evidence that neuronal circuit dysfunction is an early feature of both diseases. Impaired neuronal excitability, imbalanced excitatory and inhibitory influences, and altered functional connectivity have been reported. These phenomena are likely due to combined alterations in the various cellular components involved in the functioning of neuronal networks. This review focuses on one of these cellular components: inhibitory neurons. We assess the evidence for inhibitory neuron impairments in amyotrophic lateral sclerosis and frontotemporal dementia, as well as the mechanisms leading to the loss of inhibition. We also discuss the contributions of these alterations to symptoms, and the potential therapeutic strategies for targeting inhibitory neuron deficits.

## 1. Introduction

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive and disabling neurodegenerative disorders. ALS is characterised primarily by the degeneration of upper and lower motor neurons in the cortex, brainstem and spinal cord, which leads to muscle atrophy and progressive paralysis. Patients typically die from respiratory failure 3 to 5 years after diagnosis (Feldman et al., 2022; Ilieva et al., 2023). FTD represents a group of clinically diverse disorders characterised by a relatively selective degeneration of the frontal and temporal lobes. This results in significant alterations in behaviour, personality, executive functions, and language skills. Based on these clinical manifestations, patients are classically subdivided into subgroups, including the behavioural variant, and two variants of primary progressive aphasia (semantic or non-fluent). Patients typically die from comorbidities and undernourishment 7 to 13 years after diagnosis (Antonioni et al., 2023).

ALS and FTD constitute a pathophysiological continuum, displaying clinical, neuropathological and genetic overlaps. Pure ALS and pure FTD represent the two extreme ends of this continuum, whereas 15 % of

patients receive both diagnoses. This number may be underestimated because of the preponderance of one condition. It is now postulated that at least 50 % of patients with ALS develop behavioural and cognitive alterations, while up to 40 % of FTD patients experience motor impairments (Burrell et al., 2011; Murphy et al., 2016). Beyond this clinical overlap, ALS and FTD display common pathological abnormalities, including inclusions of TDP-43, which are present in most ALS cases and approximately half of FTD cases (Arai et al., 2006; Ling et al., 2013; Neumann et al., 2006). Finally, genes linked to ALS have also been associated with FTD. The most prominent example is C9ORF72 repeat expansion, which leads to ALS and/or FTD, sometimes within the same family (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Similarly, TARDBP mutations or TBK1 haploinsufficiency are associated with ALS, FTD, or the combination of both (Benajiba et al., 2009; Borroni et al., 2009; Cirulli et al., 2015; Freischmidt et al., 2015; Kabashi et al., 2008; Le Ber et al., 2015; Pottier et al., 2015; Sreedharan et al., 2008). However, this is not the case for all genes. Currently, SOD1 mutations are known to only cause ALS (Rosen et al., 1993), whereas GRN mutations cause FTD (Cruts et al., 2006). As there is no effective treatment available, it is imperative to elucidate the pathological causes and

**Abbreviations:** ALS, Amyotrophic lateral sclerosis; ALSFRS-R, Revised ALS functional rating scale; CSP, Cortical silent period; FTD, Frontotemporal dementia; GABA, γ-aminobutyric acid; GAD, Glutamic acid decarboxylase; KCC2, Potassium-chloride cotransporter 2; LICI, Long-interval intracortical inhibition; NKCC1, Sodium-potassium-chloride cotransporter 1; SICI, Short-interval intracortical inhibition; [¹¹C]flumazenil, Flumazenil labelled with carbon-11.

* Corresponding author.

E-mail addresses: felicie.lorenc@inserm.fr (F. Lorenc), ldupuis@unistra.fr (L. Dupuis), raphaelle.cassel@inserm.fr (R. Cassel).
mechanisms to identify therapeutic targets.

There is compelling evidence that neuronal circuit dysfunction is an early feature of both ALS and FTD. A multitude of factors contribute to the precise regulation of neuronal network development, maintenance and functioning. In particular, neuronal activity is contingent upon the intrinsic excitability of the neuronal populations, the strength of synapses, and the quantity and timing of both excitatory and inhibitory inputs. In ALS and FTD, alterations have been reported in multiple components regulating neuronal networks and activities. These encompass altered intrinsic excitability of neurons (Gunes et al., 2020), impaired excitatory and inhibitory synaptic inputs (Mora and Allodi, 2023), altered neuromodulation (Brunet et al., 2020) and dysfunctional support by glial cells (Xie et al., 2023). This ultimately results in increased cortical excitability in individuals with ALS or FTD (Vucic and Kiernan, 2006, 2017). In the spinal cord of ALS patients, the current results are less conclusive but may point towards an initial increase in the excitability of lower motor neurons (Wainger et al., 2014), which is then followed by a decrease in excitability (Devlin et al., 2015). All of these alterations influence each other and are probably accompanied by compensatory or maladaptive mechanisms. Adding to this complexity, these alterations appear to be specific to the type of cells, region of the central nervous system and stage of the disease. Identifying the initial perturbation and the sequence of events involved in ALS and FTD pathophysiology will thus be extremely challenging. A perhaps overly simplistic model suggests that ALS and FTD are characterised by an imbalance between excitation and inhibition, which is shifted towards a relatively unopposed excitation which ultimately becomes pathological.

The use of functional magnetic resonance imaging –fMRI– has produced contradictory outcomes, with studies demonstrating either increased or decreased functional connectivity in the brains of ALS patients compared with controls (Kocar et al., 2021). To elucidate this discrepancy, it has been postulated that functional connectivity may increase at early stages of the disease and then decline as the pathological burden accumulates. Electrophysiological techniques, including electroencephalography –EEG– and magnetoencephalography –MEG–, have also reported results which are consistent with increased functional connectivity in ALS. Two underlying mechanisms may explain this increase: additional brain structures may be recruited to compensate for structural damage, and/or local inhibitory circuitries may be impaired. Interestingly, this disrupted functional connectivity seems to be related to behavioural and cognitive dysfunctions (Basaia et al., 2020). Most studies including FTD patients demonstrated reduced functional connectivity, which was correlated with atrophy patterns (Dev et al., 2021).

This review examines the evidence for inhibitory neuron deficits in ALS and FTD patients, with a focus on the similarities and differences between the two diseases. To this end, we used a biochemical definition of inhibitory neurons and gathered data regarding neurons that release the two main inhibitory neurotransmitters: γ-aminobutyric acid (GABA) and glycine. Based on data obtained from patients and mouse models, we further discuss the mechanisms leading to a reduced inhibition, as well as the contribution of inhibitory neuron alterations to motor, behavioural and cognitive symptoms. Finally, we highlight potential therapeutic strategies for targeting inhibitory neurons.

# 2. Main text

## 2.1. Pathological evidence of inhibitory neuron impairments in the brains of ALS and FTD patients

### 2.1.1. Uncertainty regarding the levels of neurotransmitter

Following the initial stages of postnatal development, GABA is the principal inhibitory neurotransmitter in the brain. Given that inhibitory neurons may be affected during the pathogenesis of ALS and FTD, we hypothesise that the levels of this neurotransmitter should decrease. Indeed, significantly lower levels of GABA have been reported in the motor cortex of ALS patients compared with healthy controls using

edited proton magnetic resonance spectroscopy (Foerster et al., 2012, 2013). However, this alteration was not observed when more recent protocols were employed (Atassi et al., 2017; Weerasekera et al., 2019). In patients with ALS, Weerasekera et al. reported a significant correlation between the levels of GABA and N-acetylaspartate, which is considered a marker of neuronal integrity. In patients with FTD, GABA levels were found to be reduced in a subregion of the frontal cortex (Murley et al., 2020). Nevertheless, the assessment of GABA levels remains challenging because of the superimposition of signals for diverse metabolites and the low concentration of GABA, which results in low spatial resolution.

An alternative approach is to study the levels of key enzymes involved in neurotransmitter synthesis. Glutamic acid decarboxylase (GAD) is expressed predominantly in inhibitory neurons and is the enzyme responsible for the synthesis of GABA from glutamate. GAD mRNA levels were found to be significantly increased in the prefrontal and temporal cortices of ALS patients using in situ hybridisation histochemistry (Petri et al., 2006). This could be interpreted as a compensatory mechanism to counter a decline in inhibitory influences. Another study reported an upregulation of GAD1, encoding the GAD<sub>67</sub> isoform, in the frontal cortex of sporadic ALS patients compared with controls (Andrés-Benito et al., 2017). However, the protein levels of GAD<sub>67</sub> appeared to be unaltered. Conversely, a decrease in GAD<sub>67</sub> immunofluorescent labelling was reported in a small number of SOD1 patients (Khademullah et al., 2020).

In light of the inherent constraints associated with the direct assessment of inhibitory neurotransmitter levels, it remains challenging to ascertain whether ALS and FTD patients exhibit a reduction in these levels.

### 2.1.2. Decreased binding to GABA receptors

To circumvent the aforementioned limitations, some studies have employed indirect methods, including positron emission tomography –PET–. In particular, flumazenil labelled with carbon-11 ([¹¹C]flumazenil) is a widely used tracer for the assessment of GABAergic function in the cerebral cortex, as it binds to ionotropic GABA<sub>A</sub> receptors (Andersson et al., 2019). In ALS patients, a marked and widespread decrease in the binding of [¹¹C]flumazenil has been reported in motor and premotor regions (Lloyd et al., 2000; Turner et al., 2005a), as well as prefrontal regions (Lloyd et al., 2000). Moreover, there was a significant negative correlation between impairments in upper motor neurons and a decrease in binding over the dominant hemisphere (Turner et al., 2005a). This reduction in binding may be indicative of a loss of inhibitory and pyramidal neurons that express GABA<sub>A</sub> receptors and/or a downregulation of the expression of GABA<sub>A</sub> receptors in intact neurons (Fig. 1). These two hypotheses are discussed below.

SOD1 patients homozygous for the D90A mutation exhibit a characteristic phenotype and relatively long disease duration. Their pattern of decreased [¹¹C]flumazenil was distinct and less extensive than in sporadic patients (Turner et al., 2005a). In particular, no decrease was detected in motor regions when compared to controls. A significant correlation was reported between clusters of reduced [¹¹C]flumazenil binding and disease duration or severity score. The latter was calculated with the revised ALS functional rating scale (ALSFRS-R), a clinical scale designed to evaluate motor impairments and functional deterioration in patients (Gordon et al., 2004). It is therefore tempting to suggest that the relative sparing of inhibitory circuits may be a mechanism contributing to the slower disease progression in patients homozygous for the D90A mutation.

### 2.1.3. Loss of neurons and neurites

As an alternative indirect evaluation of inhibitory neurotransmission, several studies have focused on characterising the density and molecular markers of inhibitory neurons in ALS and FTD. The number of calbindin neurons was reported to be reduced by over 60 % in deep cortical layers of several brain regions in ALS patients compared with
<figure><img src="image_4.png" /><figcaption>Fig. 1. Main inhibitory neuron impairments reported in the brains of ALS and FTD patients.</figcaption></figure>

healthy controls (Maekawa et al., 2004). This was notably shown in the primary motor cortex and dorsolateral prefrontal cortex. In previous studies, the density of calbindin neurons was also drastically reduced in the frontal cortex of patients with ALS-FTD (Ferrer et al., 1993) or FTD (Ferrer, 1999). The post-mortem analysis conducted by Maekawa et al. further revealed trends towards a reduced density of calretinin and parvalbumin neurons. However, this result is still a topic of debate. Previous studies concluded that the soma of parvalbumin neurons is relatively well preserved in patients with ALS (Iince et al., 1993), ALS-FTD (Ferrer et al., 1993) or FTD (Ferrer, 1999). Nevertheless, a lower expression of the PVALB gene, encoding parvalbumin, was observed in the motor cortex of ALS patients in comparison to controls (Lederer et al., 2007). A recent transcriptomic analysis also revealed that neuronal markers, including calbindin, parvalbumin and vasoactive intestinal peptide -VIP-, were downregulated in the frontal and temporal cortices of FTD patients compared with controls (Hasan et al., 2022). A comparison of the estimated cellular compositions showed a significant decrease in the proportion of inhibitory neurons in the frontal and temporal cortices. This was partially associated with the neuronal loss and reduction in cortical thickness observed in the frontal cortex. Finally, the number of parvalbumin neurons was reported to be reduced by 25 % in the dorsolateral prefrontal cortex of sporadic and C9ORF72 ALS patients (Lin et al., 2021) and was found to be reduced in a small number of SOD1 patients (Khademullah et al., 2020).

To our knowledge, only one study has evaluated the presence of pathological hallmarks in cortical inhibitory neurons (Nolan et al., 2020). The authors reported that, in sporadic ALS patients, aggregates of hyperphosphorylated TDP-43 are only rarely observed in GAD<sub>67</sub>-positive inhibitory neurons.

### 2.1.4. Altered composition of GABA receptors

An additional indirect assessment of inhibitory neurotransmission is the evaluation of the composition of GABA receptors. In the brain, GABA<sub>A</sub> receptors are predominantly composed of a combination of α1-2, β1-3 and γ2 subunits. Initial studies demonstrated a significant reduction in the expression of GABRA1, encoding the α1 subunit, in the motor (Lederer et al., 2007; Petri et al., 2003), prefrontal and temporal (Petri et al., 2006) cortices of ALS patients compared with controls. This was not observed in the occipital cortex (Petri et al., 2006), which is considered to be preserved in ALS. More recently, omics studies have revealed deregulation of GABAergic signalling pathways in both ALS (Andrés-Benito et al., 2017; Aronica et al., 2015; Laszlo et al., 2022) and FTD (Jiang et al., 2018; Pottier et al., 2022). Although the findings appear to be heterogeneous, they indicate that the composition of

GABA<sub>A</sub> receptors is altered in the brains of these patients (Table 1), which may result in changes in the physiological and pharmacological properties of these receptors.

Interestingly, certain alterations appear to be specific to subgroups of ALS patients. In a transcriptomics study of the motor cortex, an unsupervised hierarchical clustering approach subdivided sporadic patients into two groups associated with distinct deregulated pathways and genes (Aronica et al., 2015). These groups were not related to technical variation or demographic factors (sex, age at onset and death, disease duration). The first subgroup exhibited a downregulation of a gene cluster associated with the life cycle of GABA<sub>A</sub> receptors. This was linked to the significant downregulation of GABRA1, GABRB1, GABRB2 and GABRG2. Conversely, the second group did not exhibit any deregulation of the GABAergic signalling pathways. Furthermore, a proteomics study of the primary motor cortex of ALS patients revealed increased levels of α5 and δ subunits (Laszlo et al., 2022). Stratifying the data by cognitive performance demonstrated that the δ subunit was upregulated in ALS patients with cognitive impairments compared to those without. Data stratified by C9ORF72 status displayed an upregulation in the α4 subunit expression in the prefrontal cortex of patients with repeat expansions in comparison to those with no mutation. These results underscore the necessity of developing methods for the identification of ALS subtypes, as considering ALS pathology as a single entity may mask the underlying pathogenic mechanisms.

G protein-coupled GABA<sub>B</sub> receptors may be relatively well preserved in ALS and FTD. These receptors are composed of two subunits, GABA<sub>B1</sub> and GABA<sub>B2</sub>, and are encoded by GABBR1 and GABBR2, respectively. Only two studies reported the deregulation of these genes in the brains of sporadic ALS patients. One study observed a reduction in GABBR1 expression in the motor cortex (Aronica et al., 2015), while the second study found an upregulation in GABBR2 in the frontal cortex (Andrés-Benito et al., 2017).

## 2.2. Neurophysiological evidence of inhibitory neuron impairments in the brains of ALS and FTD patients

### 2.2.1. Reduced inhibitory transmission

The loss of inhibitory neurons and neurites, as well as the altered composition of GABA receptors, can affect inhibitory neurotransmission. Over the past few decades, different protocols of transcranial magnetic stimulation –TMS– have been employed to assess cortical excitability in patients. Several neurophysiological parameters have emerged, including short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI) and cortical silent period (CSP).
<table><caption>**Table 1**
ALS and FTD patients display broad alterations in the composition of GABA<sub>A</sub> receptors.</caption><thead><tr><th rowspan="2">Form of disease</th><th rowspan="2">Brain region</th><th colspan="6">Transcriptomics analysis of the main GABA<sub>A</sub> receptor subunits</th></tr><tr><th>α1</th><th>α2</th><th>β1</th><th>β2</th><th>β3</th><th>γ2</th></tr></thead><tbody><tr><td rowspan="3">ALS</td><td>Motor cortex</td><td>Reduced</td><td>Unaltered</td><td>Increased</td><td>Unaltered</td><td>Unaltered</td><td>Unaltered</td></tr><tr><td>Frontal cortex</td><td>Reduced</td><td>—</td><td>Unaltered</td><td>Unaltered or increased</td><td>—</td><td>Unaltered</td></tr><tr><td>Temporal cortex</td><td>Reduced</td><td>—</td><td>Unaltered</td><td>Unaltered</td><td>—</td><td>Unaltered</td></tr><tr><td rowspan="2">FTD with TDP-43 inclusions</td><td>Frontal cortex</td><td>—</td><td>—</td><td>—</td><td>—</td><td>Reduced</td><td>—</td></tr><tr><td>Parietal cortex</td><td>—</td><td>Unaltered</td><td>Unaltered</td><td>Unaltered</td><td>Unaltered</td><td>Unaltered</td></tr><tr><td rowspan="2">FTD with MAPT mutations</td><td>Insular cortex</td><td>—</td><td>Reduced</td><td>Unaltered</td><td>Reduced</td><td>Reduced</td><td>Reduced</td></tr><tr><td>iPSC-derived cortical neurons</td><td>—</td><td>Reduced</td><td>Reduced</td><td>Reduced</td><td>Reduced</td><td>Reduced</td></tr></tbody></table>

<table><thead><tr><th rowspan="2">Form of disease</th><th rowspan="2">Brain region</th><th colspan="6">Transcriptomics (or proteomics) analysis of the other GABA<sub>A</sub> receptor subunits</th></tr><tr><th>α3</th><th>α4</th><th>α5</th><th>γ1</th><th>γ3</th><th>δ</th></tr></thead><tbody><tr><td rowspan="3">ALS</td><td>Motor cortex</td><td>Unaltered</td><td>Unaltered</td><td>Unaltered (increased)</td><td>—</td><td>Unaltered</td><td>Unaltered (increased)</td></tr><tr><td>Frontal cortex</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>Increased</td></tr><tr><td>Temporal cortex</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td rowspan="2">FTD with TDP-43 inclusions</td><td>Frontal cortex</td><td>—</td><td>—</td><td>Unaltered</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Parietal cortex</td><td>—</td><td>Unaltered</td><td>Unaltered</td><td>Unaltered</td><td>—</td><td>—</td></tr><tr><td rowspan="2">FTD with MAPT mutations</td><td>Insular cortex</td><td>—</td><td>Reduced</td><td>Unaltered</td><td>Unaltered</td><td>—</td><td>—</td></tr><tr><td>iPSC-derived cortical neurons</td><td>—</td><td>Reduced</td><td>Reduced</td><td>Reduced</td><td>—</td><td>—</td></tr></tbody></table>

Depending on the group of patients and brain region, the expression of genes encoding the different subunits is either reduced, unaltered or increased (Andrés-Benito et al., 2017; Jiang et al., 2018; Laszlo et al., 2022; Lederer et al., 2007; Petri et al., 2003, 2006; Pottier et al., 2022). This does not necessarily indicate that the expression of proteins is similarly affected. iPSC: induced pluripotent stem cells.

SICI is commonly associated with cortical inhibitory neurons acting via GABA<sub>A</sub> receptors, while LICI is mediated by long-latency inhibitory postsynaptic potentials acting via GABA<sub>B</sub> receptors (McDonnell et al., 2006; Vucic et al., 2023). CSP duration is linked to a combination of long-latency inhibitory cortical processes and spinal inhibitory mechanisms. It emerges from the activation of cortical inhibitory neurons acting via GABA<sub>B</sub> receptors, as well as glycineric inhibitory neurons in the ventral horn of the spinal cord (Skarabot et al., 2019).

The reduction in both SICI and CSP duration appears to represent a uniform pathophysiological process in ALS patients (Fig. 1, Table 2) (Higashihara et al., 2024). Interestingly, this was also observed in sporadic patients, who presented no clinical or neurophysiological evidence of lower motor neuron dysfunction (Menon et al., 2015), and in patients at the time of symptom onset (Menon et al., 2020). This suggests that cortical disinhibition is an early phenomenon in ALS pathology. Asymptomatic carriers of SOD1 mutations or C9ORF72 repeat expansion exhibited no alterations in SICI or CSP duration when compared to controls (Geevasinga et al., 2015; Vucic et al., 2008). However, Vucic et al. described three presymptomatic SOD1 mutation carriers in whom both parameters were altered months before the development of the first clinical manifestations of ALS.

Two studies reported that SICI declines with time when patients are followed longitudinally (Menon et al., 2020; Shibuya et al., 2017). This highlights the possibility that the dysfunction of inhibitory neuronal circuits evolves with disease progression and is more prominent in the later stages of ALS. However, a previous study observed the opposite phenomenon in their cohort. Patients with a limited peripheral disease burden presented a smaller SICI than patients with advanced disease (Vucic and Kiernan, 2006). Correlation analyses also reported mixed results, with SICI reduction being associated with the progression of motor impairments and functional deterioration (assessed with the ALSFRS-R) (Shibuya et al., 2017; Van den Bos et al., 2018) or not (Menon et al., 2020).

Intracortical inhibition was found to be preserved in SOD1 patients homozygous for the D90A mutation (Turner et al., 2005b), yet they exhibited similar functional disability (assessed with the ALSFRS-R) as sporadic ALS patients who had reduced intracortical inhibition. This is in line with another study in which the authors concluded that cortical, and possibly spinal, inhibitory circuits are preserved in patients with homozygous D90A mutations compared to sporadic patients (Weber et al., 2000).

<table><caption>**Table 2**
ALS and FTD patients exhibit common alterations in neurophysiological parameters linked to cortical inhibition.</caption><thead><tr><th>Form of disease</th><th>Short-interval intracortical inhibition</th><th>Long-interval intracortical inhibition</th><th>Cortical silent period</th><th>References</th></tr></thead><tbody><tr><td>Sporadic ALS</td><td>Reduced</td><td>—</td><td>Reduced</td><td>(Menon et al., 2020; Pavey et al., 2024; Shibuya et al., 2017; Van den Bos et al., 2018; Vucic and Kiernan, 2006)</td></tr><tr><td>Familial ALS with SOD1 mutations</td><td>Reduced</td><td>—</td><td>Normal</td><td>(Vucic et al., 2008)</td></tr><tr><td>Familial ALS with FUS mutations</td><td>Reduced</td><td>—</td><td>Reduced</td><td>(Blair et al., 2010)</td></tr><tr><td>Familial ALS with C9ORF72 repeat expansions</td><td>Reduced</td><td>—</td><td>Reduced</td><td>(Geevasinga et al., 2015; Williams et al., 2013)</td></tr><tr><td>FTD with a behavioural variant</td><td>Reduced</td><td>Reduced</td><td>Reduced</td><td>(Bae et al., 2016; Benussi et al., 2017)</td></tr><tr><td>FTD with primary progressive aphasia</td><td>Reduced</td><td>Reduced</td><td>Non-significant trend towards a reduction</td><td>(Benussi et al., 2017; Burrell et al., 2011)</td></tr><tr><td>FTD with C9ORF72 or GRN mutations</td><td>Reduced</td><td>Non-significant trend towards a reduction</td><td>—</td><td>(Benussi et al., 2016)</td></tr></tbody></table>

In FTD patients, the reduction in both SICI and LICI seems to be a uniform pathophysiological process (Fig. 1, Table 2). However, inconsistent results were obtained with asymptomatic carriers of GRN mutations compared with controls. A study reported no alterations in
intracortical inhibition (Benussi et al., 2016), while a second one reported a significant reduction in SICI (Gazzina et al., 2018). In both studies, the onset of clinical symptoms was estimated from the mean age at symptom onset observed in the family. This showed that SICI assessments were performed 16.8 and 18.5 years before the expected symptom onset, respectively. A third study included both symptomatic and asymptomatic carriers of GRN mutations and C9ORF72 repeat expansion, and stratified them based on the age at symptom onset or estimated years from symptom onset (Benussi et al., 2019b). With this approach, they highlighted that SICI may already be significantly reduced 25 years before the expected symptom onset, followed by a reduction in LICI 5 years later. Both neurophysiological parameters were found to decline over time, and this continued after symptom onset for SICI, while LICI tended to stabilise. The estimation of the age at symptom onset based on family history may not be applicable for all mutations (Moore et al., 2020), so one should exercise caution with the aforementioned observations.

In studies including both ALS and FTD patients, no significant differences in SICI were reported between the two groups, but defects were more pronounced in ALS than FTD (Bae et al., 2016; Burrell et al., 2011). Burrell et al. reported that one-third of FTD patients in their cohort exhibited motor deficits and one-eighth were also diagnosed with motor neuron disease. In these patients, SICI tended to be lower than in FTD patients without motor neuron disease. While inhibitory neurotransmission may be more intensively affected in ALS than in FTD patients, it may be more broadly affected in the latter. Indeed, both SICI and LICI appear to be altered in FTD.

### 2.2.2. Altered neuronal oscillations

Finally, a number of studies have used electroencephalography (EEG) and magnetoencephalography (MEG) recordings to assess neuronal oscillations in the brains of ALS and FTD patients. Beta oscillations (15–30 Hz), which can be measured at rest or during somatosensory processing and motor control, may reflect inhibitory neuron functions (Barone and Rossiter, 2021). In healthy controls, the enhancement of GABAergic neurotransmission, achieved by inhibiting the neuronal reuptake of synaptic GABA or activating GABA<sub>A</sub> receptors with diazepam, increased baseline beta power at rest, as well as beta desynchronisation during movement preparation (Hall et al., 2011; Muthukumaraswamy et al., 2013). A reduction in beta power has been reported in the sensorimotor cortex of sporadic and C9ORF72 ALS patients (Dukic et al., 2019; Trubshaw et al., 2024), as well as in the temporal, parietal, occipital and subcortical regions of the brains of FTD patients with a behavioural variant (Govaarts et al., 2022; Lindau et al., 2003). This provides further support for the concept of a diminished inhibitory neurotransmission in patients. In these cohorts, measuring beta desynchronisation during movement preparation did not allow to draw a definitive conclusion, as this parameter was inconsistently found to be reduced (Bizovićar et al., 2014; Hughes et al., 2018), unaltered (Riva et al., 2012), or increased (Proudfoot et al., 2017). Beta resynchronisation after movement may depend on GABA<sub>B</sub> receptors, as it was reduced by increased synaptic concentrations of GABA (Muthukumaraswamy et al., 2013), but not upon the activation of GABA<sub>A</sub> receptors (Hall et al., 2011). Post-movement beta resynchronisation was observed to be diminished in ALS (Bizovićar et al., 2014; Proudfoot et al., 2017; Riva et al., 2012) and FTD (Hughes et al., 2018) patients compared with controls. In ALS, this reduction was found to be negatively correlated with the extent of corticospinal damage, and may be associated with reduced cortical inhibition (Riva et al., 2012). In particular, the results of these clinical studies have been interpreted as indicating a difficulty in reaching a state of decreased neuronal excitability after movement cessation. In the motor cortex of healthy controls, a positive correlation was identified between post-movement beta resynchronisation and bulk GABA concentrations (Gaetz et al., 2011), which may reflect inhibitory neuron and synapse densities, rather than synaptic activity per se. It may therefore be hypothesised that the

diminished resynchronisation is also associated with a reduced density of inhibitory neurons and synapses in patients. Overall, the altered cortical beta oscillations lend support to the idea that inhibitory systems may be dysfunctional in ALS and FTD.

## 2.3. Pathological evidence of inhibitory neuron impairments in the spinal cords of ALS patients

### 2.3.1. Loss of neurons and neurites

In the lumbar spinal cords of sporadic ALS patients (Fig. 2), the density of interneurons was found to be reduced by 53 % compared with controls (Stephens et al., 2006). This has been studied in the dorsomedial region of the ventral horn grey matter, where it was not possible to differentiate between excitatory and inhibitory interneurons. Similarly, a variable but substantial loss of synapses was observed in the ventral horn of the spinal cord, but not in the dorsal and intermediate laminae (Aousji et al., 2023). The extent of synaptic loss demonstrated a strong correlation with disease duration; however, this study did not differentiate between excitatory and inhibitory synapses. A previous study reported a loss of calbindin-positive soma and axons (Ince et al., 1993). In the ventral horn white matter, a significant loss of parvalbumin- and calretinin-positive axons has been found in sporadic ALS patients compared with controls (Hayashi et al., 2013). This reduction was equal to 83 % and 74 %, respectively. It is noteworthy that the number of calretinin-positive soma was not affected.

### 2.3.2. Altered composition of GABA receptors

Following the initial stages of postnatal development, glycine is the principal inhibitory neurotransmitter in the spinal cord. In particular, dorsal inhibitory neurons largely co-express GABA and glycine, whereas ventral inhibitory neurons are mainly glycineric. The data currently available on the composition of GABA or glycine receptors in the spinal cords of ALS patients remain limited and inconsistent. A reduction in GABRE expression, encoding the GABA<sub>A</sub> receptor δ subunit, was reported in a cohort of patients, which included sporadic cases, one familial case with a SOD1 mutation, and one familial case with an unidentified mutation (Dangond et al., 2004). However, another study reported the main deregulated gene clusters in the ventral horn of the lumbar spinal cords of sporadic patients, and this did not include GABAergic or glycineric signalling pathways (Andrés-Benito et al., 2017). More recently, a proteomics analysis revealed a downregulation of pathways linked to synaptic signalling and diverse synapse subtypes, including GABAergic synapses, in the cervical spinal cords of sporadic patients and patients with C9ORF72 repeat expansions (Aly et al., 2023).

## 2.4. Neurophysiological evidence of inhibitory neuron impairments in the spinal cords of ALS patients

The H reflex is a valuable tool for evaluating the excitability of inhibitory neuronal circuits in the spinal cord (Knikou, 2008). Distinct inhibitory circuits can be assessed using different paradigms and were found to be altered in ALS patients (Fig. 2). Recurrent inhibition, which is mediated by Renshaw cells and allows negative feedback important for movement control, is significantly decreased in patients compared with controls (Castro et al., 2024). It has been proposed that this inhibition is enhanced at early stages of the disease and serves as a protective mechanism, particularly in patients with slow progression of lower limb dysfunctions (Sangari et al., 2022). Additionally, recurrent inhibition was found to be unaltered in patients with no lower limb dysfunction, while it was reduced in patients with motor weakness in the lower limbs (Özyurt et al., 2020; Sangari et al., 2022). GABAergic neurons located in the dorsal horn mediate the presynaptic inhibition of primary sensory afferents, which has been observed to be reduced in ALS patients (Castro et al., 2024; Howells et al., 2020; Özyurt et al., 2020). Finally, the postsynaptic inhibition induced by cutaneous stimulation is mediated by glycineric synapses, and was also found to be reduced in ALS (Castro
<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Spinal inhibitory neurons involved in locomotor control, and main alterations reported in ALS patients. In the dorsal horn, several populations of inhibitory neurons are involved in sensory pathways, and can form connections with primary sensory afferents. In the ventral horn, V1 neurons (which include V1 Renshaw cells and V1 Ia neurons) and V2b neurons form ipsilateral connections with motor neurons. Of note, all V1 neurons express the transcription factor Engrailed-1, while V1 Renshaw cells also express parvalbumin and calbindin, and V1 Ia neurons express parvalbumin. Commissural dorsal VO~D~ neurons and dl6 neurons form contralateral connections with motor neurons.</figcaption></figure>

et al., 2024).

## 2.5. What is the relationship between impairments in inhibitory neurons and symptoms of ALS and FTD?

Neuronal circuit dysfunction has been proposed as an early feature of both ALS and FTD and may be an important step in the pathogenesis of these diseases. Clinical studies have highlighted correlation between inhibitory neurons impairments and motor, behavioural and cognitive symptoms in patients. However, most of the causal relationships remain to be investigated.

### 2.5.1. Inhibitory neuron impairments are associated to specific motor symptoms in ALS patients

The split-hand phenomenon is a specific clinical feature of ALS, characterised by the weakness and wasting of muscles located at the base of the thumb (thenar muscles) and the relative preservation of muscles located at the base of the little finger (hypothenar muscles). It was suggested that the reduction in intracortical inhibition, but not peripheral dysfunctions, contribute to the development of this phenomenon (Menon et al., 2014). Notably, reductions in short-interval intracortical inhibition and cortical silent period duration were observed when motor responses were recorded across all muscles, but were most prominent with recordings over the thenar muscles.

### 2.5.2. Inhibitory neuron impairments are correlated with behavioural phenotypes in FTD patients

Behavioural disinhibition is a common feature of FTD and is associated with decreased functional independence and increased mortality. Challenging behaviours probably originate both from a lack of

comprehension of the appropriateness of actions in a given social context and an altered motor inhibition. The absence of effective symptomatic treatments reinforces the need to understand the mechanical links between neuropathology, brain function and behaviour.

A significant correlation was reported between a reduction in intracortical inhibition (assessed with transcranial magnetic stimulation) and an increase in disinhibited and aggressive behaviours in FTD patients with a behavioural variant or primary progressive aphasia (semantic and non-fluent) (Benussi et al., 2020). This correlation was stronger in patients with GRN mutations than in those without. Upon detailed examination of the behaviours, SICI reduction was found to be associated with aggressivity, irritability, poor judgement and impulsivity, restlessness, obsessive behaviour, hoarding, excessive jocularity, hyperorality, hypersexuality and incontinence. Conversely, apathetic behaviours were associated with a decrease in intracortical facilitation, which reflects the activity of excitatory glutamatergic circuits. These results thus suggest that disinhibited symptoms may originate from the reduced activity of inhibitory circuits. Another study demonstrated that decreased GABA and glutamate concentrations were associated with increased disinhibited behaviour, characterised by impaired response inhibition measured by a stop-signal task (Murley et al., 2020). However, in this cohort, no associations were found between GABA concentrations and social disinhibition or challenging behaviours reported by carers. This discrepancy may be attributed to the fact that GABA levels are difficult to assess and were evaluated in a specific subregion of the frontal lobe, while numerous other regions are implicated in the behavioural impairments reported by carers.

In FTD patients with a behavioural variant, increased disinhibited behaviours were also strongly associated with reduced movement-related beta desynchronisation and resynchronisation when they
needed to generate and inhibit responses during a stop-signal task (Hughes et al., 2018). As stated before, this neurophysiological alteration may be a proxy of inhibitory neuron dysfunctions.

### 2.5.3. Inhibitory neuron impairments are correlated with cognitive phenotypes in ALS and FTD patients

In ALS patients, the assessment of [¹¹C]flumazenil binding in specific frontal and temporal areas demonstrated a correlation between reduced binding and decreased performance on a written verbal fluency task and naming task (Wicks et al., 2008). Based on the protocol used and the lumbar onset of motor symptoms, these results appear to be exclusively linked to cognitive alterations, including executive and language defects. A previous study showed that cerebral activation was impaired in ALS patients compared with controls during word retrieval processes (assessed with both letter fluency and naming tasks) (Abrahams et al., 2004). Depending on the region, functional magnetic resonance imaging revealed increased or decreased cerebral activity, but inhibition remains to be more precisely assessed.

A transcriptomics study recently revealed reduced expression of CPLX1, encoding complexin-I, in the frontal cortex of FTD patients with TDP-43 inclusions, regardless of the presence of GRN mutations (Pottier et al., 2022). Complexin-I is a presynaptic protein relatively enriched in GABAergic inhibitory terminals. It regulates the assembly of SNARE proteins and, in turn, synaptic vesicle exocytosis. In patients with Alzheimer's disease, decreased levels of complexin-I have been linked to lower cognitive performance (Ramos-Miguel et al., 2017) and increased rate of cognitive decline (Boyle et al., 2013). Therefore, it would be interesting to further investigate the consequences of this decrease on the cognitive performance of FTD patients.

## 2.6. What are the mechanisms leading to decreased inhibition in ALS and FTD?

Several underlying mechanisms may account for the observed impairments in cortical and spinal inhibitory circuits (Fig. 3). Given the complex and multifactorial nature of ALS and FTD, which involve different cell types, it is plausible that a combination of mechanisms is at play, or that specific mechanisms are associated with particular subtypes of ALS and FTD. The following paragraphs present a summary of the mechanisms that have been proposed based on studies conducted with mouse models.

### 2.6.1. Presynaptic transcriptional alterations leading to inhibitory neuron dysfunction and death

Transcriptional alterations, which have been reported in patients

and mouse models, could influence cell fate and neuronal activity in inhibitory neurons. In the spinal cord of *SOD1*<sup>G93A</sup> mice, early and parallel reductions in the expression of *extended synaptotagmin 1* (Mora et al., 2024) and *engrailed-1* (Montañana-Rosell et al., 2024) were recently reported in V1 inhibitory neurons. This was followed by downregulation of inhibitory neurotransmitter markers (Montañana-Rosell et al., 2024) and cell death (Allodi et al., 2021; Chang and Martin, 2009) at later stages of the disease. Extended synaptotagmin 1 is a presynaptic protein which has been linked to the promotion of synaptic growth when overexpressed, and to reduced neurotransmission when mutated (Kikuma et al., 2017). Engrailed-1 appears to be an essential maintenance factor for the survival of postmitotic dopaminergic and serotoninergic neurons, possibly by preventing apoptosis (Albéri et al., 2004; Fox and Deneris, 2012; Simon et al., 2001). The early loss of these genes may thus contribute to the dysfunction and degeneration of V1 neurons. Of note, in zebrafish carrying a mutant *Sod1* gene, spinal glycineergic neurons were found to be vulnerable at early stages of embryonic development (McGown et al., 2013). These neurons were the first cell type to exhibit translational modifications related to the activation of a stress response, which was followed by dysregulation of glycine release.

### 2.6.2. Postsynaptic transcriptional alterations modifying the composition of inhibitory receptors

A number of mouse models have been observed to recapitulate the altered composition of GABAA receptors, which is a feature present in *post-mortem* brain tissues from ALS and FTD patients. This may ultimately impair the functionality of these receptors and, thereby, the inhibitory neurotransmission. FUS was found to be localised in both pre- and postsynaptic compartments, where it binds to several RNAs encoding GABA receptor subunits, and may be directly involved in the regulation of protein translation, including the translation of the GABAA receptor α1 subunit (Sahadevan et al., 2021). In the cortex of FUS<sup>ΔNLS/+</sup> mice, the authors observed an early synaptic accumulation of FUS, which was accompanied by a downregulation of GABAA receptor α3 subunit protein levels, followed by a transient upregulation of GABAergic genes and proteins in unstable synapses (Sahadevan et al., 2021; Scekic-Zahirovic et al., 2021). This increased transcription may be seen as a compensatory mechanism that is directly linked to the accumulation of FUS and the stabilisation of RNAs by FUS binding. At late stages of the disease, molecular and ultrastructural alterations of inhibitory synapses have been reported, but the underlying mechanisms remain to be studied.

Similarly, genes encoding subunits of the GABAA and GABAB receptors (including Gabrb2, Gabrb3, Gabrg2 and Gabbr1) were found to be

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Several mechanisms, likely to be complementary, could account for the decreased inhibition in ALS and FTD. Cl⁻: chloride; KCC2: potassium-chloride cotransporter 2; NKCC1: sodium-potassium-chloride cotransporter 1.</figcaption></figure>
downregulated in the brains of tauP301L mice compared to control mice (Jiang et al., 2018). Restricted expression of a mutant human MAPT gene in forebrain excitatory neurons was found to be sufficient to alter inhibitory synapses via non-cell autonomous mechanisms (Shimojo et al., 2020). In particular, a loss of GABAergic synapses was observed in the cortex and hippocampus, and this was accompanied by a reduction in the levels of pre- and postsynaptic GABAergic proteins, including the GABA<sub>A</sub> receptor α1 subunit. During the ageing process, these protein levels were comparable between mutant and control mice, indicating that compensatory mechanisms may have occured.

In addition, inhibitory receptors were found to be altered in the spinal cords of *SOD1*<sup>G93A</sup> mice. An early reduction in *Gabra5* expression was observed, accompanied by a loss of GABAergic boutons on the membrane of bulbar motor neurons (Venugopal et al., 2023). A previous in vitro study of spinal motor neurons obtained from embryos also proposed that alterations in the expression and functionality of GABA<sub>A</sub> receptors may occur (Avossa et al., 2006). However, to date, in vivo studies have not reported significant impairments in spinal GABAergic inhibition. Conversely, alterations in glycine inhibition have been documented. The density of glycine-evoked currents was found to be significantly smaller in cultured motor neurons prepared from *SOD1*<sup>G93A</sup> embryos compared to control motor neurons (Chang and Martin, 2011). This was accompanied by a decreased density of glycine receptors on motor neurons and a reduction in the expression of the gene encoding the α1 subunit.

### 2.6.3. Abnormal elimination of inhibitory synapses by microglia

In the brains of Grn<sup>-/-</sup> mice, the loss of progranulin has been linked to an excessive age-dependent activation of microglia (Lui et al., 2016). This was associated with increased production and accumulation of complement proteins in both excitatory and inhibitory synapses, while the enhanced synaptic pruning activity of microglia selectively eliminated inhibitory synapses. Although the underlying mechanisms still need to be studied, two hypotheses have been proposed. It is possible that excitatory and inhibitory synapses exhibit different expression profiles of complement receptors and/or different intrinsic properties, which influences the efficacy of engulfment by microglia.

### 2.6.4. Abnormal depolarising action of GABA

In immature neurons, high expression of sodium-potassium-chloride cotransporter 1 (NKCC1) results in a high concentration of intracellular chloride ions (Kaila et al., 2014). This facilitates the efflux of chloride ions when GABA and glycine receptors are activated, thereby inducing depolarisation of the membrane potential. During development, a switch occurs, allowing hyperpolarisation of the membrane potential upon the activation of inhibitory receptors. This is due to the upregulated and abundant expression of potassium-chloride cotransporter 2 (KCC2) in mature neurons, which results in a low concentration of intracellular chloride ions, and an influx of chloride ions when GABA and glycine receptors are activated. An increase in NKCC1 expression and a decrease in KCC2 expression have been associated with epilepsy, as well as several neurodegenerative and neuropsychiatric disorders (Ben-Ari, 2017; Lam et al., 2023).

In the lumbar spinal cords of *SOD1*<sup>G93A</sup> mice, a reduction in KCC2 expression was observed at the membrane of vulnerable motor neurons (Fuchs et al., 2010). This process started during the late presymptomatic phase and accelerated as the disease progressed. A more recent study reported decreased expression of KCC2 at the membrane of cortical and spinal motor neurons in presymptomatic *SOD1*<sup>G93A</sup> and *TDP-43*<sup>A315T</sup> mice (Khademullah et al., 2023). It is noteworthy that the administration of KCC2 enhancers restored its membrane expression and function, postponed the onset of motor deficits, and prolonged the lifespan of *SOD1*<sup>G93A</sup> mice by 50 days. Additionally, the authors reported that KCC2 expression was diminished at the membrane of cortical motor neurons in *SOD1*, *C9ORF72*, and sporadic ALS patients. These results suggest that a switch could occur from hyperpolarising to depolarising GABA, which

would decrease the inhibitory influence of this neurotransmitter.

### 2.6.5. Exacerbated inhibition of inhibitory neurons

To allow tight regulation of their influence, inhibitory neurons are interconnected: they can synapse on excitatory motor neurons to provide direct inhibition but can also synapse onto other inhibitory neurons and consequently have an indirect facilitatory effect, which is called a disinhibitory effect (Tremblay et al., 2016). One can thus imagine that the initial impairment of the upstream subpopulation of inhibitory neurons induces a cascade of consequences and an indirect alteration of motor neurons. In line with this hypothesis, the density of somatostatin neurons was found to be decreased, while their activity was increased in the motor cortex of presymptomatic *TDP-43*<sup>A315T</sup> mice compared with control littermates (Zhang et al., 2016). Conversely, the density of parvalbumin neurons was not altered, but their activity was decreased. As somatostatin neurons are known to regulate parvalbumin activity, the authors proposed that the enhanced activity of somatostatin neurons increased their inhibitory influence on parvalbumin neurons, which, in turn, disinhibited layer 5 pyramidal neurons, leading to their increased excitability and degeneration. Interestingly, the ablation of somatostatin neurons in *TDP-43*<sup>A315T</sup> mice restored the spiking activity of pyramidal neurons to physiological levels. This was followed by a significant increase in the density of GABAergic synapses on these neurons, and this prevented neuronal loss.

### 2.7. Contribution of inhibitory neuron impairments to symptoms

To our knowledge, the causal relationship between inhibition deficits and motor symptoms has been evaluated in mouse models by several research groups, while the contribution of inhibitory neuron impairments to behavioural or cognitive symptoms has yet to be investigated in ALS and FTD models. Mice lack Betz cells and von Economo neurons (Bakken et al., 2021; Seeley et al., 2012), which are the main degenerating neurons in the frontal cortex of ALS and FTD patients, respectively. Additionally, their corticospinal tract is anatomically and functionally different than in humans (Lemon, 2008). However, network activity and degeneration can still be recapitulated in mice.

#### 2.7.1. Inhibitory neurons influence motor neuron activity and death in ALS mouse models

In ALS, ocular motor neurons are considered resilient because they do not degenerate. Several studies have compared these neurons with vulnerable brainstem and spinal motor neurons to identify potential protective mechanisms. In healthy humans, mice and rats, resilient motor neurons have distinct transcriptional profiles, with marked differences in genes involved in GABAergic synaptic transmission (Brockington et al., 2013). Several genes encoding GABA<sub>A</sub> and GABA<sub>B</sub> receptor subunits were found to be upregulated in the three species under investigation. In particular, an enrichment of the GABA<sub>A</sub> receptor α1 subunit was observed in resistant motor neurons, while vulnerable motor neurons were enriched in the α2 subunit (Comley et al., 2015; Lorenzo et al., 2006). In addition, resilient motor neurons showed a decreased ratio of glycine receptor density to GABA<sub>A</sub> receptor density, as well as an elevated density of extrasynaptic GABA<sub>A</sub> receptors in healthy rats (Lorenzo et al., 2006). Finally, resilient motor neurons exhibited reduced susceptibility to excitotoxicity, which was mediated in part through enhanced GABAergic transmission (Brockington et al., 2013). Collectively, these results suggest that inhibitory synaptic transmission differs between resilient and vulnerable motor neurons, and may underlie their differential vulnerability. This hypothesis has recently been supported by the study of a mouse model in which human TDP-43 is mislocalised primarily in forebrain excitatory neurons. In these mice, the increased excitability of upper motor neurons was followed by a degeneration of lower motor neurons in lumbar regions 1 to 3, but not in lumbar regions 4 to 6. Interestingly, an increased inhibitory innervation was observed specifically in lumbar regions 4 to 6, where lower motor
neurons were spared, potentially due to protective mechanisms associ-
ated with the inhibitory system (Reale et al., 2023).

Moreover, the impairment of inhibitory neurons may directly
contribute to the altered activity and degeneration of motor neurons
(Fig. 4). The density of GABAergic synapses was found to be reduced in
the somatic area of layer 5 pyramidal neurons in the motor cortex of
presymptomatic TDP-43<sup>A315T</sup> mice compared with control littermates
(Zhang et al., 2016). Measurements of miniature and evoked inhibitory
postsynaptic currents from pyramidal cells demonstrated a significant
reduction, whereas excitatory transmissions remained unaltered. In
addition, pyramidal neurons exhibited increased excitability, which
could be abolished by blocking GABA<sub>A</sub> receptors. This was followed by
signs of dendritic alterations and neurodegeneration at the onset of
symptoms. Similar observations were reported for presymptomatic
SOD1<sup>G93A</sup> mice. In the motor cortex of these mice, decreased density and
activity of parvalbumin neurons were found, accompanied by increased
excitability of pyramidal motor neurons (Khademullah et al., 2020).
Interestingly, increasing the activity of parvalbumin neurons during the
late presymptomatic and symptomatic phases normalised pyramidal cell
excitability to control levels and effectively delayed the onset of motor
impairments, as evidenced by a delayed decline in muscle strength. This
ultimately extended survival by almost 20 days.

In the spinal cords of presymptomatic *SOD1*<sup>G93A</sup> mice, it was
demonstrated that inhibitory neurons undergo transcriptional changes
prior to those observed in excitatory neurons (Montañana-Rosell et al.,
2024). One of the lost markers is engrailed-1, which is a transcription
factor expressed by V1 neurons and transferred from these cells to motor
neurons (Lebœuf et al., 2023). Both the decreased expression of
engrailed-1 and the neutralisation of extracellular engrailed-1 resulted in
a loss of motor neurons and decreased limb strength. This may therefore
be another mechanism linking the loss of inhibitory synapses to the
progression of ALS.

2.7.2. *Inhibitory neurons contribute to locomotor phenotypes in ALS mouse models*

In the spinal cords of presymptomatic *SOD1*<sup>G93A</sup> mice, a selective loss of glycinergic synapses on fast motor neurons has been reported (Allodi et al., 2021). This was accompanied by a progressive slowing of locomotor speed, an inability to maintain locomotion, and a hyperflexion of the hindlimbs. These phenotypes emerged prior to the observed decline in grip strength and the degeneration of motor neurons. In addition, the silencing of V1 inhibitory neurons positive for engrailed-1 in wild-type mice resulted in the aforementioned phenotypes. In *SOD1*<sup>G93A</sup> mice, the stabilisation of V1 inhibitory connections was sufficient to rescue motor neuron loss and ameliorate motor phenotypes, but this did not prevent weight loss or death (Mora et al., 2024). From this, it is evident that other altered neuronal circuits are involved in the pathogenesis of ALS, thereby reinforcing the necessity to develop a combination of therapies to address all symptoms. Nevertheless, these studies strongly indicate that inhibitory neurons play a pivotal role in the initial stages and development of locomotor changes (Fig. 4).

2.8. *Future directions: inhibitory neurons as a possible therapeutic target*

As detailed in this review, several alterations in inhibitory neurons
have been documented in the brains and spinal cords of ALS and FTD
patients, as well as in mouse models. Interestingly, these impairments
may contribute to the development and/or progression of certain core
symptoms that characterise these two neurodegenerative diseases. This
hypothesis has been primarily investigated in ALS models, in which a
reduction in cortical and spinal inhibitory influences has been linked to
alterations in motor neurons and/or changes in locomotor function
(Allodi et al., 2021; Khademullah et al., 2020; Zhang et al., 2016). The
question of whether alterations in inhibitory neurons can cause behav-
ioural and cognitive deficits in ALS and FTD remains unanswered. This

<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Impairments of inhibitory neurons influence the development of locomotor deficits in ALS mouse models. Impairments of inhibitory neurons result in impairments of cortical and spinal motor neurons via a proven (solid arrow) or assumed (dashed arrow) cause-and-effect relationship.</figcaption></figure>
topic is of particular interest given that the reduced intracortical inhibition and altered oscillatory dynamics have been associated with disinhibited and aggressive behaviours (Benussi et al., 2020; Hughes et al., 2018), which has the potential to worsen the prognosis of FTD patients. Overall, the current data justifies the necessity of investigating whether targeting deficits in cortical and spinal inhibition would efficiently alleviate certain symptoms. The development of new therapeutic approaches to stabilise or enhance the inhibitory activity will be challenging owing to the complexity and heterogeneity of inhibitory neuronal populations and circuits. Further investigation is also needed to elucidate all the mechanisms underlying the reduced inhibitory influence in ALS and FTD. Nevertheless, this represents a promising avenue for further research, as discussed below.

In ALS mouse models, enhancing or stabilising the inhibitory activity effectively attenuated locomotor impairments (Fig. 5), thus offering an encouraging therapeutic approach. In particular, the fact that analogous mechanisms have been documented in TDP-43 and SOD1 mice suggests that inhibitory neurons may represent a relevant target in ALS cases associated with different causative genes and proteins, and even in patients for whom the aetiology of the disease remains unknown.

It is noteworthy that the augmentation of cortical, but not spinal, inhibitory activity in ALS mouse models extended their survival (Khademullah et al., 2020; Mora et al., 2024). In sporadic ALS patients within two years of disease onset, reduced short-interval intracortical inhibition has been identified as an independent factor associated with shorter survival (Shibuya et al., 2016). This reduction was not found to be a prognostic factor when including patients at a later disease stage. However, this could be explained by the reduced number of patients with long disease durations and a possible change in intracortical inhibition during disease progression. In the total cohort, the estimated median survival was 28 months for patients with the smallest intracortical inhibition values and 36 months for patients with the highest values.

## 2.9. Increasing the activity of GABA receptors in ALS patients

A limited number of drugs are currently available to treat ALS, and

their effects on disease progression are moderate (Evans et al., 2024). Riluzole was the first pharmaceutical compound approved by the Food and Drug Administration -FDA- in 1995 and the European Medicines Agency -EMA- in 1996. It is now postulated that this sodium channel blocker increases the median survival of patients by 6 to 19 months (Andrews et al., 2020), while exerting neuroprotective effects through several mechanisms of action. In particular, riluzole is thought to restore the balance between excitation and inhibition, notably by reducing synaptic GABA reuptake (Mantz et al., 1994) and potentiating postsynaptic GABA<sub>A</sub> receptor function (He et al., 2002; Jahn et al., 2008). In ALS patients, riluzole partially normalises intracortical inhibition (Vucic et al., 2013), but this effect is transient (Geevasinga et al., 2016).

Retigabine (or ezogabine) is a potassium channel activator which has been approved for the treatment of focal-onset epilepsy (Gunthorpe et al., 2012). This compound has multiple mechanisms of action, including the potentiation of postsynaptic GABAA receptor responses. In ALS patients, a single dose of retigabine was sufficient to reduce the excitability of motor axons to a greater extent than a single dose of riluzole (Kovalchuk et al., 2018). Recently, retigabine was used in a phase II clinical trial including 55 patients with ALS, resulting in a dose-dependent reduction in the excitability of both cortical and spinal motor neurons and a 53 % increase in short-interval intracortical inhibition (Wainger et al., 2021). However, the effect on disease progression remains to be investigated.

Given that none of the aforementioned compounds act solely by increasing the activity of GABA receptors, it is possible that the beneficial effects observed in ALS patients, whether currently or in the future, may be due to other mechanisms of action.

## 2.10. Regulating neuronal activity in ALS and FTD patients

In ALS patients, the external modulation of excitatory and inhibitory neurotransmission has the potential to mitigate motor impairments, notably by promoting growth factors which enhance neuroplasticity and by possibly slowing the degeneration of neuronal circuits. A two-week course of transcranial direct current stimulation -tDCS- applied to both motor cortices and spinal cords was found to improve global

<figure><img src="image_8.png" /><figcaption>**Fig. 5.** Enhancing or stabilising the inhibitory activity represents a promising therapeutic approach to alleviate locomotor deficits. In ALS mouse models, activating inhibitory neurons or stabilising inhibitory synapses results in the protection of cortical and spinal motor neurons and delays motor symptoms.</figcaption></figure>
muscle force and quality of life (Benussi et al., 2019a). More recently, this non-pharmacological intervention has yielded encouraging results regarding the patient survival, a potential reduction in neurofilament levels and the modulation of cortical excitation and inhibition (Benussi et al., 2023). This current stimulation may modulate superficial neuronal populations and, in turn, facilitate the increase in short-interval intracortical inhibition while reducing intracortical facilitation (Vignaud et al., 2018).

In FTD patients, the external modulation of inhibitory neuron activity and the induction of gamma oscillations could represent a promising therapeutic approach to slow the neurotoxicity and death of pyramidal cells. An intervention based on 40 Hz transcranial alternating current stimulation –tACS– is currently being tested in patients with a behavioural variant (Assogna et al., 2022). This non-invasive brain stimulation is thought to restore altered brain oscillatory patterns and, in turn, to improve working memory, attention and cognitive functions. In addition, it would be interesting to assess whether a long-term effect on disinhibitory behaviours can be elicited with this approach.

## 3. Conclusion

Over the past two decades, a growing body of clinical and experimental evidence has highlighted the contribution of inhibitory neuron impairments to the ALS-FTD continuum. Degeneration of inhibitory neurons and neurites, as well as alterations to pre- and postsynaptic inhibitory markers, have been documented in the brains of patients. However, post-mortem investigations remain constrained in their ability to elucidate the temporal sequence and potential functional consequences of these alterations. Interestingly, neurophysiological studies have revealed a reduction in cortical inhibitory transmission, which appears to be an early feature of both ALS and FTD. The precise alterations may differ among patients carrying different pathological mutations and/or exhibiting different forms of the diseases. Nevertheless, it has been proposed that ALS and FTD are both characterised by an imbalance between excitation and inhibition, with the former being relatively unopposed and ultimately becoming pathological. Although this model is arguably overly simplistic, it reinforces the idea that ALS and FTD belongs to a continuum, in which both diseases share pathological mechanisms, as evidenced by the damage to inhibitory neurons. Studies on the spinal cord of ALS patients are less extensive, and the current findings appear to be more heterogeneous. However, some of them also point towards a reduced inhibition. Given that inhibitory neuron alterations have been observed in a number of mouse models of ALS and FTD, several underlying mechanisms have been proposed to explain the impairments in cortical and spinal inhibitory circuits. It remains unclear whether specific mechanisms are associated with sub-types of ALS and FTD, or whether they all combine. More importantly, the alterations in inhibitory neurons may play a pivotal role in the development and/or progression of motor, behavioural and cognitive symptoms, thus becoming potential therapeutic targets. As a consequence, further investigation of inhibitory neurons in ALS and FTD would be beneficial for advancing our understanding of these diseases, and potentially improving their management.

## Funding

Financial support was received for the writing and publication of this article. FL was supported by a doctoral fellowship from the Ministry of Higher Education, Research and Innovation, the Fondation Anne-Marie et Roger Dreyfus under the aegis of the Fondation de France (grant agreement no. 00129231/PR-145778) and the Association pour la Recherche sur la Sclérose Latérale Amyotrophique.

## Ethics approval and consent to participate

Not applicable.

## Consent for publication

Not applicable.

## Availability of data and material

Not applicable.

## CRediT authorship contribution statement

Félicie Lorenc: Writing – review & editing, Writing – original draft.
Luc Dupuis: Writing – review & editing, Writing – original draft.
Raphaëlle Cassel: Writing – review & editing, Writing – original draft.

## Declaration of competing interest

The authors declare that they have no competing interests.

## Acknowledgements

Figures were created with BioRender.com.

## Data availability

No data was used for the research described in the article.

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