# Functional myelin in cognition and neurodevelopmental disorders

Hasni Khelfaoui, Cristobal Ibaceta-Gonzalez, Maria Cecilia Angulo

► To cite this version:

Hasni Khelfaoui, Cristobal Ibaceta-Gonzalez, Maria Cecilia Angulo. Functional myelin in cognition and neurodevelopmental disorders. Cellular and Molecular Life Sciences, 2024, 81 (1), pp.181-10.1007/s00018-024-05222-2. doi:10.1007/s00018-024-05222-2

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Functional myelin in cognition and neurodevelopmental disorders

Hasni Khelfaoui¹, Cristobal Ibaceta-Gonzalez¹, Maria Cecilia Angulo¹,²

¹ Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266,

"Team: Interactions between neurons and oligodendroglia in myelination and myelin repair", F-75014

Paris, France

² GHU-PARIS Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014 Paris, France

**Corresponding author:**

María Cecilia Angulo, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM 1266, 102, rue de la Santé, 75014 Paris, FRANCE. Tel: 33-1-40789243. e-mail address: maria-cecilia.angulo@u-paris.fr
31 ABSTRACT

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33 In vertebrates, oligodendrocytes (OLs) are glial cells of the central nervous system (CNS) responsible
34 for the formation of the myelin sheath that surrounds the axons of neurons. The myelin sheath plays
35 a crucial role in the transmission of neuronal information by promoting the rapid saltatory
36 conduction of action potentials and providing neurons with structural and metabolic support.
37 Saltatory conduction, first described in the peripheral nervous system (PNS), is now generally
38 recognized as a universal evolutionary innovation to respond quickly to the environment: myelin
39 helps us think and act fast. Nevertheless, the role of myelin in the central nervous system, especially
40 in the brain, may not be primarily focused on accelerating conduction speed but rather on ensuring
41 precision. Its principal function could be to coordinate various neuronal networks, promoting their
42 synchronization through oscillations (or rhythms) relevant for specific information processing tasks.
43 Interestingly, myelin has been directly involved in different types of cognitive processes relying on
44 brain oscillations, and myelin plasticity is currently considered to be part of the fundamental
45 mechanisms for memory formation and maintenance. However, despite ample evidence showing the
46 involvement of myelin in cognition and neurodevelopmental disorders characterized by cognitive
47 impairments, the link between myelin, brain oscillations, cognition and disease is not yet fully
48 understood. In this review, we aim to highlight what is known and what remains to be explored to
49 understand the role of myelin in high order brain processes.
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52 **Keywords:** myelin, cognition, oligodendrocytes, OPCs, development, schizophrenia, autism spectrum

53 disorder, brain oscillations
54

# INTRODUCTION

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In the central nervous system (CNS), oligodendrocytes (OLs) are responsible for the production and maintenance of the myelin sheath. OLS originate from oligodendrocyte precursor cells (OPCs), which arise in the embryonic (ventral OPCs) and perinatal (dorsal OPCs) mouse telencephalon in distinct successive waves [1, 2]. OPCs also persist as a major pool of progenitors in the adult brain long after oligodendrogenesis completion and promote remyelination when necessary [3–9]. However, OPCs should not be constrained to their OL progenitor function as they are arising as circuit regulators in the parenchyma with functions ranging from neuronal migration to glial scar formation ([10] extensively reviews these non-canonical functions). Along the same line, an extensive body of evidence links OLS to a variety of roles such as energy metabolism, neuroprotection, axonal maintenance and information processing [11–14]. Although OLS and the myelin sheaths they generate are considered a single cellular entity, functional studies often discriminate between roles strictly related to the cells themselves and those specifically associated with myelin *per se*.

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The myelin sheath is a highly specialized multilamellar membrane that wraps axons. Central myelin is structured by an ensemble of compact interconnected lamellae of membrane that contact the axon through terminal loops forming the axo-glial paranodal junction directly followed by the juxtaparanode located beneath the compacted myelin of the internode [15, 16]. What we usually refer to as the myelin sheath is the single entity formed by the paranodes, juxtaparanodes and the internode (Fig. 1). Adjacent myelin sheaths are separated by nodes of Ranvier (NORs) [17], unmyelinated regions where the nerve fiber is laid bare and frequently contacted by other glial cells including astrocytes [18, 19], OPCs that contact both the node and paranodal myelin and whose role is yet to be resolved [20] and finally, microglia that could play a role in remyelination when myelin sheath integrity is impaired [21, 22] (Fig. 1). Myelin's high compartmentalization allows a distinctive sheath-axon interaction that serves various functional ends such as the distribution of glial
metabolites [16, 23]. In intimate relationship with the unmyelinated segments or NORs, the myelin
sheath enables action potential regeneration and propagation along fibers of varying lengths,
resulting in saltatory conduction, an energy-, space- and time-saving phenomenon.

The function of myelin can be approached at two different levels: at the local level, which
consists of insulating axons, supporting them and ensuring bidirectional axo-glial communication,
and at the global level, which orchestrates the interconnection of neuronal assemblies and the
association of functional brain hubs for complex information processing. In this review, we will first
introduce some general concepts about the role of myelin in action potential conduction and axonal
metabolism (local level). Next, we will discuss how myelin partakes in cognitive processes and assess
whether myelination might modulate neuronal network activity and cortical oscillations during the
execution of these processes (global level). Finally, we will address the relevance of myelin defects in
neurodevelopmental disorders (NDDs) associated with cognitive deficiencies.

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92 GENERALITIES ON MYELIN IN CONDUCTION AND METABOLIC COUPLING

Saltatory conduction has long been held as the main phenomenon resulting from myelin
sheath wrapping around electrically active axons [24, 25]. In electrophysiological terms, myelin works
such wonders by decreasing the capacitance of the axolemma while increasing resistance to ion flow.
This achieves two important features: (1) conduction speed of action potentials is increased while (2)
their electrical properties are maintained throughout the traveled distance. Beyond physical
insulation of the axon, the segregation of crucial proteins by the various segments of the sheath
directly impacts conduction. Voltage-gated Na⁺ channels (Na⁺ channels) are exclusively stabilized at
the NORs by the paranodal axo-glial junction [26, 27] (Fig. 1). In this small, well-defined region of the
axon, an increase in membrane potential up to the threshold potential induces Na⁺ channels
opening, generating the strong depolarization (or rising phase) characteristic of the action potential.
Na<sub>v</sub> channels are expressed throughout the brain but their isoform combinations, density and pattern of expression differ in GABAergic interneurons as compared to glutamatergic neurons due to the morphological and functional differences of these two populations. A significant distinction between the two cell types in the rodent cerebral cortex is that GABAergic interneurons primarily express Na<sub>v</sub>1.1, while glutamatergic neurons predominantly express Na<sub>v</sub>1.2 and Na<sub>v</sub>1.6. Additional differences also emerge during development and vary across species [28, 29]. During action potential generation, Na<sub>v</sub> channels rapidly inactivate allowing K<sup>+</sup> channels to repolarize the axon. Different voltage-gated K<sup>+</sup> channels as well as mechano- and thermo-sensitive K<sup>+</sup> channels, two-pore-domain potassium (K2P) channels, actively drive repolarization (or falling phase) at the nodes [30–32], wherein K<sub>v</sub>1 channels located in the juxtaparanode contribute to the refractory period [33, 34] (Fig. 1). Similar to Na<sub>v</sub> channels, the expression patterns of K<sup>+</sup> channels may vary depending on the developmental stage and specific cell types. While certain channels, such as K<sub>v</sub>1 and K<sub>v</sub>7, can be expressed on the axons of both glutamatergic and GABAergic neurons [34, 35], K<sub>v</sub>3 channels are particularly suited to supporting the high-frequency repetitive firing characteristic of GABAergic fast-spiking interneurons (although their expression is not solely associated with this function) [36]. Regarding K<sup>+</sup> homeostasis, OL express inwardly rectifying K<sup>+</sup> channels (K<sub>ir</sub> channels) actively participating in K<sup>+</sup> buffering and contributing to OL-axon metabolic coupling [37, 38]. They also drives the establishment of axolemma resting potential allowing OLs to indirectly adjust neuronal excitability, a phenomenon especially relevant in white matter tracts where astrocytes, the main actors of extracellular potassium uptake, have limited access to axons [39]. Beyond action potential propagation at the nodal axolemma, the myelin sheath also forms a singular structure with the insulated internodal axolemma and appears to generate potentials through the periaxonal and paranodal domains thus forming another axonal conducting pathway outside of NORs. This phenomenon, termed “submyelin conduction”, could play a role in the spatiotemporal profile of
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action potential saltation [40], further supporting the notion of an electrophysiological coupling
between the axon and its myelin sheaths.

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As well as promoting fast conduction, myelin sheaths have emerged as a central component
of axon metabolism [14]. Axonal access to energy-rich extracellular metabolites is limited by myelin
insulation, so it is the myelin itself that has to supply the energy. Reminiscent of the astrocytic
"lactate shuttle", OLs transport lactate, a product of aerobic glycolysis, through the periaxonal space
into the axon via a pair of specialized monocarboxylate transporters (glial MCT1 and axonal MCT2)
allowing a myelin-axon metabolic crosstalk that is relevant in both health and disease [14, 41, 42].
This axo-glial coupling is highly plastic and follows axon energy needs through the retroactive action
of axons on their myelin sheath. Notably, neuronal activity probably increases glutamate levels in
the periaxonal space and activates NMDA receptors expressed in the paranodal and internodal
membranes of OLs, enabling them to tune their energy production to neuronal activation [43, 44].

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Beyond energy provision, myelinating cells secrete various neuroprotective and neuro-supportive
factors into the periaxonal space. For instance, glutamate activation of glial NMDA receptors triggers
the secretion by OLs of exosomes carrying specific protein and RNA cargos that are endocytosed by
neurons, improving oxidative stress resistance and long-term axonal integrity maintenance [45, 46].
Although the nature of these cargos and the signaling cascades they elicit in the axon remain largely
unknown, some have been identified such as ferritin heavy chain (FTH1), a strong iron chelator
protein that is secreted by OLs into the adjacent extracellular space to prevent ferroptosis, the
accumulation of free iron ions that generates harmful oxidizing species [47]. Although the functional
and metabolic coupling between myelin sheaths and axons is important for the dynamics of myelin-
axon interactions, its significance goes far beyond local crosstalk, as it determines the action
potential waveform and affects neuronal coding and activity in a network, ultimately influencing
information processing in the brain. Over the last decade, myelin has emerged as an important
151 component of plasticity, memory and learning, moving away from its primary function associated
152 with the transmission and velocity of action potentials.

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**Figure 1. Myelin sheath, nodal architecture and axo-glial contacts.** Axons bear multiple myelin sheaths originating from mature oligodendrocytes and consisting of the internode, juxtaparanodes and the paranodes which directly flank the nodes of Ranvier (top). Sheath architecture plays a crucial role in the segregation of nodal proteins, especially voltage-gated Na⁺ and K⁺ channels, participating in the generation of a nodal structure that is essential to action potential conduction and maintenance. Finally, the NORs are also contacted by other glial cells such as astrocytes, microglia and OPCs (bottom). They constitute a dynamic region of the axolemma and a site of modulations that serve many functional and structural purposes.
The cortex contains a patchwork of differentially myelinated axons belonging to both glutamatergic and GABAergic neurons. Presence and extent of myelination relies in part on axon diameter, as OLS tend to extensively myelinate larger axons [48, 49]. However, complex patterns of myelination are also present in sub-diameter threshold axons while some axons with the required diameter are discontinuously myelinated or not myelinated at all. Beyond axonal diameter, other factors could be driving myelination heterogeneity, notably in gray matter: OL intrinsic properties [50], axonal permissive cues [51] and somatodendritic repulsive cues [52], neuronal activity [53–58], as well as localization and cell type [59, 60]. Comparing GABAergic and glutamatergic neurons has revealed compelling differences in myelin content and patterns. On one hand, high throughput electron microscopy that individually traces pyramidal cell proximal axons in the mouse somatosensory cortex uncovered a myelin gradient, with deep layer (V/VI) pyramidal cells displaying a higher myelin coverage compared to superficial layer (II/III) pyramidal neurons. Furthermore, superficial layer pyramidal cells display a distinct longitudinal myelin pattern with myelin sheaths being separated by long unmyelinated gaps (much longer than NORs) (Fig. 2A, right; [60]). On the other hand, a vast majority of myelinated gray matter GABAergic axons belong to parvalbumin-expressing neurons (PV interneurons) [59, 61, 62]. Moreover, the extent of PV interneuron myelination appears to be proportionally scaled to the overall myelin content across different cortical areas [63] PV interneuron myelin topography is dictated by axonal diameter and interbranch distances in both human and rodent neocortex [64]. However, this myelination is limited to the proximal part of the axon (<3%), so that most of the axon is free of myelin [59], suggesting the existence of other subtle interactions between OLS and specific axonal regions (Fig. 1A, right). As PV interneurons have only short local projections, their myelination was at first quite puzzling but has since been shown to serve a cardinal role in their functional maturation. Indeed, an early disruption of PV interneuron-OPC synapses results in a dysmyelination and an abnormal proximal axon morphology. These defects are associated with a decrease of their high firing frequency and a
disturbance of their synaptic connectivity that reduces the inhibitory drive of the somatosensory cortex, specifically in layer IV [65]. Furthermore, impairing myelination early in development (as early as postnatal day 21 in mice) reduces their autaptic responses, i.e. a reduction in functional GABAergic synapses of the PV interneuron onto itself. In turn, this absence of autaptic control results in an exacerbated excitability of PV interneurons, which become unable to sustain optimal high frequency firing rates [66]. Another compelling function of PV interneuron myelin sheaths is the clustering of mitochondria and thus the fine tuning of metabolic requirements during axonal activation [67]. Interestingly, other GABAergic neuron subtypes such as a fraction of somatostatin (SST)-expressing interneurons and, to a much lesser extent, vasoactive intestinal peptide (VIP)-expressing interneurons have myelin sheaths with layer-specific arrangements [63, 68, 69]. However, the functional and structural significance of this myelination, sometimes limited to a single internode per axon, remains largely unexplored, pointing to avenues for further investigation. Nevertheless, it has recently been reported that a myelin loss in SST interneurons in the hippocampus can be associated with a reduction in their firing frequency [69]. Finally, comparisons between seven different GABAergic and glutamatergic neurons show significant variations in the myelination patterns, with PV interneurons and thalamocortical axons exhibiting higher myelination probabilities [63]. The cell identity, the axon diameter and the axonal degree of branching (collateral formation) dictate the myelin profile along axons belonging to distinct neuronal subtypes [63, 64].

We would like to highlight two important ideas: 1) although white matter myelin has been extensively studied both in health and disease, we should exert caution when extending such findings to gray matter myelination which is protracted, sparse and, as shown above, has topographical and functional complexities less found in white matter tracts [70] and 2) OL lineage cells heterogeneity (thoroughly reviewed in [71]) could be an active driver of myelination heterogeneity and should be considered in future studies.

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218 Myelination in the CNS happens in a specific spatial and temporal order in both humans and
219 rodents, and remains plastic and adaptive throughout life [72]. Myelin maturation in the brain
220 progresses in a protracted fashion, from caudal to rostral, so that the prefrontal cortex (PFC) in both
221 humans and rodents is still undergoing myelination well into early adulthood [73–78]. It is thus
222 tempting to parallel this “late” maturation of the PFC in terms of myelination with the establishment
223 of higher cognitive functions such as self-identity, social and emotional regulation, memory, adaptive
224 responsiveness and predictive decision making [54, 79, 80]. In fact, correlation between white matter
225 changes and cognitive function over the course of human life establishes a link between myelin
226 development and cognitive development. Longitudinal brain imaging studies have shown that white
227 matter volume –reflecting the myelin content and axonal caliber [81]– has a linear increase
228 throughout childhood and adolescence ([82] reviews such findings while discussing various myelin
229 imaging techniques and their shortcomings). As first reported by fractional anisotropy, a measure of
230 white matter volume in diffusion tensor imaging (DTI), an increase of myelin thickness in frontal
231 white matter positively correlates with increased working memory scope in children [83]. This was
232 further confirmed by probing working memory through the maturation of fronto-parietal and fronto-
233 striatal white matter tracts from childhood to early adulthood which revealed that proper
234 myelination of these tracts predicts future working memory capacity [84, 85]. In terms of social-
235 emotional skills in humans, a recent study on children aged 0 to 36 months positively correlates
236 myelination expansion in regions of the “social brain”, such as the medial PFC (mPFC), with social-
237 emotional development [86]. Similarly, in mice sociability is related to myelination of mPFC as shown
238 by the deleterious effects of social isolation immediately after weaning on both adult mPFC function
239 and myelination [87]. During development, exposure to an early stress caused by maternal
240 separation induces a premature differentiation of OLs in the mPFC along with emotional and object
241 recognition impairments in the adult that can be rescued by the chemogenetic activation of mPFC
242 neurons during the two first weeks of life [88]. As for other mPFC-related behavioral outputs,
243 studying myelin signals in adolescent healthy subjects offers a more complete (and complex) parallel
244 between myelin content in both gray and white matter with compulsive and impulsive behaviors
245 [89]. The expression of both behaviors was positively correlated with reduced myelin signals in
246 frontal areas such as the lateral and medial PFC [90]. Interestingly, the correlation was more
247 pronounced for gray matter regions, further supporting the notion of discrete differences in
248 myelination development and macrostructure between gray and white matter areas.

249 Myelination is therefore a long-lasting process that represents a perfect "substrate" for the
250 maturation and adaptability of cognitive processes. However, although myelination and cognitive
251 development correlate, the underlying mechanisms that link these two processes are not yet fully
252 understood. Among many of the possible mechanisms, early neuron-OL interactions may play a
253 decisive role in both developmental myelination and neuronal maturation. In the developing
254 neocortex, OPCs receive transient synaptic inputs from GABAergic interneurons, mainly PV
255 interneurons, that disappear in juvenile mice [91, 92]. The genetic inactivation of these neuro-glial
256 synapses at an early stage of postnatal development does not have a major impact on OPC
257 proliferation and differentiation, but leads to significant defects in interneuron myelination and in
258 the maturation of cortical inhibitory circuits, affecting sensory discrimination [62, 65]. Furthermore,
259 early GABA<sub>B</sub> receptor-mediated signaling onto OPCs induces the apoptosis of interneurons via the
260 cytokine TWEAK pathway, resulting in proper PV interneuron cell density and myelination in the
261 adult [93]. The specific ablation of these receptors in OPCs is associated to an excitation-inhibition
262 imbalance in the mPFC and severe social behavior defects [93]. These studies highlight an important
263 role of early interneuron-OPC communication in the establishment of cortical inhibitory circuits and
264 cognitive function (Fig. 2A).

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267 Beyond development, myelin remodeling has now emerged as one of the main drivers of
268 plasticity in the brain. Myelin establishment during critical periods of early postnatal life is indeed
269 paramount but not immutable, as OLs drive different myelination patterns in response to neuronal
270 activity and experience throughout an individual's life, thus driving a dynamic and adaptive
271 remodeling of neuronal circuits [94, 95].

272 Motor learning has been extensively used as a straightforward tool to question myelin
273 remodeling in the adult brain. In a first study on new motor skills acquisition in the rodent, Magnetic
274 Resonance Imaging (MRI) fractional anisotropy revealed that motor training induces structural
275 changes in the white matter of the motor cortex, and these positively correlated with the rate of
276 learning [96]. Preventing new myelin formation in the young adult (P60 and P90) by inhibiting new
277 OLs formation directly hinders new motor skill learning [97]. Myelin plasticity concerns motor axons
278 activated by learning and proceed in distinct steps. Amidst learning, pre-existing myelin sheaths
279 retract, generating a new pattern of intermittent myelination. After the learning phase, new myelin
280 sheaths are added to cover large unmyelinated gaps on the axolemma, forming regions of
281 continuous myelination [98].

282 Recent data on other brain areas involving higher cognitive processing and memory also
283 reveal that myelin plasticity is necessary for proper behavioral performances and outcomes. For
284 instance, spatial memory consolidation during a Morris water maze task, resulting from a complex
285 dialogue between PFC areas, such as the anterior cingulate cortex (ACC), and the hippocampus is
286 altered when *de novo* myelination is prevented in the adult [99]. Along the same line, fear learning
287 and working memory tasks (radial arm maze) appear to increase OPC proliferation and myelination in
288 the mPFC and ACC, respectively [100, 101], while inhibition of myelin formation impairs fear memory
289 recall [101]. Another study has reported that the deletion of the transcription factor Olig2 in OPCs
290 inhibits myelination, thereby impairing spatial memory in young adult mice [102]. In another register,
291 prolonged social isolation in the adult specifically induces a decrease in myelin thickness and nuclear heterochromatin in mPFC together with a social defeat phenotype, while social re-integration for four weeks resulted in a recovery of myelin transcripts and social interaction behavior [103]. 292 293 Moreover, social isolation in juvenile animals drives a hypomyelination phenotype that can be reversed in the adult by re-socialization with socially housed mice, but not socially isolated mice [87, 295 296 104], further supporting a role of myelin in driving social behavior adaptability. Myelination also affects synaptic transmission and the excitation-inhibition balance [65, 105, 106], thus having a potential impact on cortical oscillations and cognition (Fig. 2; see next section). 297 298

299 Cognitive processing in the adult brain thus most probably relies on the interplay of existing myelin modifications in response to neuronal activity as well as new myelin formation. In turn, myelination will adjust conduction velocity resulting in differential spike-timings that could underlie dynamic neuronal processing [65, 98, 107–109]. It should be noted, however, that these modifications may involve subtle mechanisms that go beyond a simple increase or decrease in the amount of myelin, as they may primarily produce a marked change in the length of NORs. Such a change has been observed in the adult mouse brain following a repetitive transcranial magnetic stimulation or the execution of 8-arm radial arm maze task [110]. It should also be considered that it is difficult to disentangle the molecular and cellular pathways as well as the exact role of each player of the myelination process (OPC, OL or myelin) in the observed neuronal and cognitive processing alterations and that further investigation is needed. 300 301 302 303 304 305 306 307 308 309

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311 BRAIN OSCILLATIONS, MYELIN AND COGNITION

312 The cerebral cortex exhibits sustained activity, characterized by rhythms or oscillations 313 spanning a wide frequency range from 0.05Hz to 500Hz [111]. Each frequency band can be 314 modulated differently by cognitive processes. Slow oscillations (0.05Hz to 30Hz) involve coordinated 315 activity of widespread neuronal ensembles, while high-frequency oscillations (30-500Hz), like gamma
oscillations (30-90Hz), are more localized and crucial for information coding (Fig. 2B, left). In particular, gamma oscillations arise from fast synchronization of excitatory neuronal activity, modulated to a large extent by PV interneurons, acting as a pacemaker to time network discharges [111-113]. Despite variations in brain size across species, gamma rhythms maintain a consistent frequency range and are modulated by cognitive mechanisms such as attention, working memory, cognitive flexibility and social cognition (Fig. 2B and C; [114]). Furthermore, different rhythms can interact, as in the phase-amplitude coupling observed between theta and gamma rhythms which has an impact on cognitive functions like working memory [115].

As mentioned before, myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks. By its capacity to speed up action potentials and mediate proper spike-timing, it has been widely assumed that myelin influences the synchronization of neuronal ensembles in the brain (Fig. 1B, right). On a broader scale, myelin architecture in humans correlates strongly with functional connectivity mediated by neuronal oscillations in the beta and low-gamma bands, reinforcing the idea of a close relationship between myelination and specific functional networks [116]. However, despite emerging evidence for the role of myelin in cognitive processes involving coupling and synchrony, only few studies have attempted to disentangle its impact on the generation and maintenance of brain oscillations. Nevertheless, myelin plasticity offers a mechanism for modifying conduction delays in an activity-dependent manner, potentially optimizing rhythmic activity in the brain [109]. Mathematical modeling and simulations have addressed this question and proposed that myelin facilitates the synchronization of axon spikes coming from distant populations of neurons whose activity is correlated [117]. The model predicts that myelin plasticity in response to local action potentials of myelinated axons adjusts the spike temporal dispersion that occurs across these individual axons, thereby optimizing the precision of axonal discharges and promoting synchrony. Although this work supports a role for myelin in the generation of cortical oscillations, the
mechanism linking myelination and neuronal synchronization is probably more complex. In vivo
analyses of the auditory system revealed that dysmyelination resulted in expected conduction delays
and desynchronization of inputs, along with a potential misdistribution of axonal channel proteins at
NORs. Interestingly, it was shown in the same study that OL-dependent metabolic deficits,
independently of myelin content and other significant structural alterations in the axon, also
disrupted the temporal precision of neuronal spikes, akin to those observed in dysmyelinated mice
[12]. This suggests the necessity of axoglial metabolic support for temporal auditory processing.
Moreover, the heterogeneity of myelination patterns, which is patchy in pyramidal cells [60] and
restricted to the proximal part of the axon in PV cells of the cortex (Fig., 2A, right; [59]), probably has
an impact on axonal conduction and needs to be taken into account. In another experimental study
using a cuprizone-induced demyelination mouse model, Dubey et al., assessed the role of myelin in
the generation of oscillations in the primary somatosensory cortex [106]. They observed that
demyelination selectively amplifies theta power during periods of quiet wakefulness (but not active
states) and proposed that this effect was caused, at least in part, by a decrease in the excitability of
PV interneurons and fast GABAergic transmission. Furthermore, during the in vivo optogenetic
stimulation of PV interneurons at a low gamma frequency of 30 Hz, local field potential recordings
revealed that this stimulation entertains an oscillatory activity at this frequency in control mice.
However, following demyelination, the same optogenetic stimulation did not modulate or maintain
the gamma rhythm. By simultaneously recording the ACC region and the hippocampus immediately
after contextual fear conditioning, Steadman et al. show that the coupling between spindle
oscillations in the prefrontal cortex and sharp wave ripple oscillations in the hippocampus was
increased in controls but unchanged in mice with a disrupted oligodendrogenesis [99]. These results
indicate that the production of new OLs is required for learning-induced increases in coordinated
hippocampal-cortical activity. However, this effect is probably not due to myelin deficiencies since it
occurs just after training.
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Despite sparse studies on the role of myelin in the synchronization of neuronal networks and brain rhythms, how myelin influences different brain oscillations during behavior, especially during cognitive processes, is largely underexplored. Local in vivo electrophysiological recordings in behaving mice with genetically determined or induced alterations in myelination would be necessary to unravel how myelin is involved in behaviorally modulated cortical rhythms. The detection and quantification of brain oscillations is an advanced field of neuroscience that allows multiple brain areas to be recorded simultaneously, in some cases using more than a thousand electrodes, while the animal performs a cognitive task. This type of studies represents a major challenge and a future line of research in the field of myelin.
A
Excitation-inhibition balance

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Myelination heterogeneity

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Oscillations

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Brain region 1

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Brain region 2

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Cognition

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Social interaction

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**Figure 2.** Summary of myelination effects at cellular, network and cognitive levels. **A.** Myelination patterns (myelin in red) of pyramidal neurons (pyr, purple) and PV interneurons (PV, blue) are different in the cortex, probably including the mPFC (right). It has been shown that myelination can affect the excitation-inhibition balance (left, [65]). However, it is unknown how myelination heterogeneity impact conduction and synaptic transmission. IL and PL: infralimbic and prelimbic regions of the mPFC; ACC: anterior cingulate. **B.** Myelin may adjust the synchrony between neuronal ensembles of two distant brain regions (right). The synchrony of local (intracortical) and inter-regional neuronal networks generates brain oscillations at different frequencies such as gamma and theta, respectively (left). **C.** Myelin appears to be important for the proper performance of cognitive tasks such as social interactions. Behavioural performance also highly depends on brain oscillations which, in turn, are influenced by myelination.

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As an early onset phenomenon with a protracted evolution throughout life, myelination has emerged as a potential key player in NDDs, disorders that have their onset during childhood and adolescence. These two critical periods of development represent sensitive time windows for environmentally induced modifications and damage to central myelin structure and functions. Here we discuss the involvement of myelin in Autism Spectrum Disorders (ASD) and schizophrenia, two major NNDs characterized by overlapping symptoms such as communication difficulties and social withdrawal.

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Autism Spectrum Disorders

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As a classic example of NDD etiology, consisting of a mix of genetic and environmental risk factors, an accumulating body of evidence demonstrates that myelin deficits underlie altered communication between major brain hubs in ASD individuals [118]. As demonstrated by Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI), white matter disruptions are widespread in children and adolescents with ASD [119–121]. Intriguingly, the white matter of autistic patients is overgrown during the first two years of life, but tends to be smaller than controls as they age [122]. These observations in humans were recently confirmed and termed “precocious myelination” in a murine model of ASD (BTBR mice) in which the number of OLs and myelin content in the frontal brain of neonatal pups was increased [123]. This accelerated postnatal development of the brain in ASD patients that tends to normalize and worsen with age might be more nuanced for gray matter myelination. It has been shown using T1w and T2w MRI that the overall spatial patterns of intracortical myelin distribution are similar between ASD children, aged 1.5 to and 5.5 years old, and compared to typically developing children, but the age-related increase in intracortical myelination is impaired in ASD children [124]. At the cellular level, OPCs cultured from a mouse model of ASD (Pten<sup>m3m4</sup>) have an enhanced proliferation rate and a premature maturation onto OLs [125]. This maturation defect does not lead in vivo to a greater number of OLs in the adult, as these
cells die by apoptosis and produce abnormal myelin which fails to ensheath axons [125]. In another mouse model of ASD induced by the prenatal exposure to valproic acid, OL density and myelin content is decreased in adult mice in some of the main brain regions linked to social behavior, such as the mPFC, pyriform cortex and basolateral amygdala [126]. Integrated transcriptomic analyses of both ASD mouse models and ASD patients tissues further stress OL gene dysregulation and myelination defects across species, as a highlight in both syndromic and idiopathic ASD [127, 128]. Another area of interest concerns myelin proteins such as MBP, that has been put forward as targeted by an abnormal autoimmune reaction in the ASD brain [129]. However, while molecular and cellular alterations in OL biology and myelination are a hallmark of ASD, it is unknown whether these are responsible for social behavior deficits in the disease. Interestingly, frontal cortex myelin thickness reduction has been associated with a murine model of Williams syndrome (WS), a non-canonical NDD characterized by hypersociability [130], proving that conflicting behaviors, hypersociability in WS, compared to hyposociability in ASD, can arise from similar myelin abnormalities (hypomyelination), further stressing the complex etiology and symptomatology of such diseases.

These studies in ASD have singled out myelin and myelinating cells as potential therapeutic targets in a few preclinical studies. Promyelinating compounds such as clemastine -which promotes OPC differentiation into OLs and has been studied as a promyelinating agent in other myelin-related disorders such multiple sclerosis [131]- appear to rescue the cellular, structural and behavioral phenotype of the ASD mouse model of Pitt-Hopkins syndrome [132], opening new and exciting areas of investigation for future therapies. Furthermore, in a mouse model of perinatal hypoxia (a condition commonly associated with ASD in humans), which exhibits significant myelination impairments, early environmental enrichment was also shown to selectively promote endogenous myelin regeneration and functional recovery in the developing white matter [133]. Therefore, an
439

alternative therapeutic strategy to improve myelination and white matter dysfunction might be the
early behavioral intervention and environmental enrichment.

440

441

442

## Schizophrenia

443

Schizophrenia (SCZ) onset coincides with adolescence and early adulthood, but its origins
can be traced back to earlier stages of development as some cognitive impairments, depression and
negative symptoms can occur during childhood [134]. Many evidence suggest that myelin alterations
are as prevalent in this disease as they are in ASD. Although the neurobiological mechanisms
underlying SCZ are not fully understood, it has been proposed that genetic and environmental risk
factors during the perinatal period, either *in utero* or in infancy, contributes to neurodevelopmental
abnormalities that may lead to impaired myelination in the adult brain [135]. The use of myelinating
cells and myelin as a prism to look at this disorder is compelling because myelination is a protracted
developmental process in most of the brain regions found to be dysfunctional in SCZ [80, 135].

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448

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Myelination impairments during development have been considered to result in a defective maturation of neuronal networks connectivity (the 'dysconnectivity' hypothesis), which could explain some of the varying cognitive symptoms in SCZ patients, including impaired cognitive flexibility [136-139]. Similarly to ASD, imaging studies questioning the structural integrity of white matter and the inter-connectivity of various brain regions have provided a better understanding of structural insults in SCZ patients [80]. Although most of the metrics used in imaging can be related to various structural components of white matter (axon diameter, fiber density, myelination), foundational work investigating both total and frontal white matter regions suggested an overall hypomyelination of the corpus callosum in human SCZ patients [140]. These findings were corroborated by post-mortem analyses of the anterior frontal cortex which showed a reduction in the expression of the two OL-associated proteins, MAG and CNPase, in SCZ patients [140]. It was subsequently observed that frontal white matter is indeed recurrently defective in chronic patients [141-143]. On the other
464

hand, a recent study focusing on gray matter highlights more complex changes with some regions
exhibiting higher and others lower myelin content in first-episode treatment-naïve SCZ patients
[144].

465

466

467

Recent genetic, epigenetic and biochemical analyses have corroborated OL dysfunction and
abnormal expression of myelin-related genes and proteins [145, 146] as well as a decrease in the
density of OLs in layer V of the PFC in SCZ patients [147]. As compared to normal OPC numbers, a
reduction in OL density hints at a differentiation impairment of OPCs in the PFC of these patients
[148]. Moreover, SCZ-like behaviors in juvenile mice such as impaired sociability can be elicited *via* a
DNA hypermethylation, a hallmark risk factor of SCZ, that targets genes related to OL lineage cells
[149]. Overall, dysfunctional OL lineage cells could explain, to some extent, myelination insult of SCZ
patients although many interrogations remain as to the origins of such disorders and their temporal
unfolding, ultimately asking if dysmyelination is a cause or a result of SCZ [135, 142]. An important
point of discord from human studies is the difficulty of untangling the mesh of possible myelin insults
as studies include a heterogenous population of patients: chronic patients that have been medicated
for years, first episode patients naïve for any treatment, high risk patients, familial genetic risk
patients. They are usually age and gender matched with the controls but might still account for slight
contradictory results. A standardization of patient cohorts is needed to confirm previous results and
produce finer insight in the investigations. Although further research is needed on this regard, a
recent report demonstrated that specific mutations in chondroitin sulfate proteoglycan 4
(CSPG4/NG2), a hallmark protein of OPCs, exhibited familial segregation in SCZ patients having
significant abnormal white matter integrity [150], a finding in favor of a direct role of OL lineage cells
in this disease.

468

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471

472

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474

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476

477

478

479

480

481

482

483

484

485

486

All these studies stress the role of myelin in connecting functional hubs for the
synchronization of distant neuronal ensembles and the production of optimal behavioral responses
to a changing environment. Brain connectivity analyses indeed indicate that long-range connectivity

487

488
489 is usually impaired in SCZ. Along with white matter integrity impairments, another substantial
490 evidence supports a causal role of local GABAergic interneuron dysfunction in linking cortical circuit
491 and behavioral deficits in this disorder [151]. Several reports have found that alterations in local
492 oscillations, mainly gamma oscillations, occur during performance of cognitive control tasks [151-
493 153]. As previously mentioned, synchronization of cortical networks in the gamma band frequency is
494 modulated to a large extent by the activity of PV interneurons, which provide robust perisomatic
495 inhibitory control of glutamatergic neurons [154, 155]. This probably explains why dysfunctions in PV
496 interneuron and gamma oscillations have been associated with cognitive deficits characteristic of SCZ
497 [151, 156, 157]. Interestingly, myelination defects occurred specifically in PV interneurons of the
498 mPFC in a rat model displaying schizophrenia-like behaviours [158]. Considering these findings, the
499 high levels of myelination of PV interneurons and the early and reciprocal interactions between
500 cortical PV interneurons and OPCs, it might be possible that impairments in PV interneuron
501 myelination compromise the integrity of precisely timed action potentials and local synchronization
502 [159, 160]. An interesting line of study in the field of myelin will be to investigate whether PV
503 interneuron and OL lineage abnormalities can synergize to increase the risk of developing NDDs.

504 Much like in ASD, myelination could be a potential biological target in SCZ. In this line, pro-
505 myelinating drugs could be evaluated, for example, as precognitive interventions in first-episode
506 patients. Antipsychotic drugs that could act on OL dysfunction by potentiating their differentiation
507 and maturation, such as the NMDA receptor ligand D-serine, and lithium [161] are another area of
508 excitement in terms of SCZ treatment, just like we previously discussed with promyelinating
509 compounds as possible therapies for ASD.

510
511 **Declarations**

512 **Ethics approval**

513 No experimental data requiring approval is presented.

514

515 **Consent for publication**

516 All authors have given consent for publication.

517

518 **Availability of data and material**

519 No data presented.

520

521 **Competing interests**

522 The authors have declared that no competing interests exist.

523

524 **Funding**

525 This work was supported by grants Fondation pour la Recherche Médicale (FRM, EQU202103012626), ANR CoLD (ANR, ANR-20-CE16-0001-01) and ANR Myelex (ANR, ANR-21-CE37-0020). M.C.A. is a CNRS (Centre National de la Recherche Scientifique) investigator.

528

529 **Authors' contributions**

530 All authors contributed to the conception of the article and wrote the manuscript.

531

532

533

534

535
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