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# Astroglial regulation of critical period plasticity in the developing brain

Jérôme Ribot, Rachel Breton, Glenn Dallérac, Nathalie Rouach

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Jérôme Ribot, Rachel Breton, Glenn Dallérac, Nathalie Rouach. Astroglial regulation of critical period plasticity in the developing brain. Current Opinion in Neurobiology, 2025, 94, pp.103092. 10.1016/j.conb.2025.103092. hal-05404529

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# Astroglial regulation of critical period plasticity in the developing brain

Jérôme Ribot¹, Rachel Breton¹,², Glenn Dallérac² and Nathalie Rouach¹

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Astrocytes emerge as pivotal regulators of brain plasticity during critical periods (CPs) of development. Beyond their traditional roles in supporting neuronal function, astrocytes actively shape synaptic circuits maturation and remodeling during postnatal experience-dependent plasticity. Through mechanisms such as regulation of the extracellular matrix or synaptic pruning, astrocytes influence the timing and extent of plasticity across sensory and cognitive systems. These processes have been demonstrated in various animal models and forms of plasticity, indicating that these glial cells play a conserved role across species. Such findings unveil the dynamic and central role of astrocytes in coordinating the complex interplay between neural circuits and external stimuli during critical windows of brain development.

## Addresses

¹ Neuroglial Interactions in Cerebral Physiology and Pathologies, Center for Interdisciplinary Research in Biology, Collège de France, CNRS, INSERM, PSL-Neuro, Université PSL, Paris, France

² Astrocytes et Cognition, Institut des Neurosciences de Paris-Saclay, CNRS UMR 9197, Université Paris-Saclay, Orsay, France

Corresponding authors: Ribot, Jérôme (jerome.ribot@college-de-france.fr); Rouach, Nathalie (nathalie.rouach@college-de-france.fr)

**Current Opinion in Neurobiology** 2025, 94:103092

This review comes from a themed issue on **Cellular Neuroscience 2024**

Edited by **Takao Hensch** and **Cristina Alberini**

For complete overview of the section, please refer the article collection
- Cellular Neuroscience 2024

Available online 14 August 2025

https://doi.org/10.1016/j.conb.2025.103092

0959-4388/© 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Introduction

Critical periods (CPs) are specific time windows in early postnatal development during which neural circuits exhibit heightened plasticity in response to environmental stimuli. The concept was originally introduced by Hubel and Wiesel [1], who demonstrated ocular dominance (OD) plasticity after monocular deprivation (MD) in kittens' visual cortex. These periods have been

observed in various species and are essential for the proper maturation of sensory, motor, and cognitive systems [2,3], allowing the brain to fine-tune its circuitry based on experiences. Once the CP ends, the potential for plasticity diminishes, and neural circuits become more resistant to changes, promoting stability in brain function. Disruption in the timing of these CPs, either by premature closure or delayed onset, is associated with neurodevelopmental disorders such as autism or schizophrenia [4].

Astrocytes play an essential role in neural circuits, actively participating at the synaptic, cellular, and network levels [5,6]. At the synaptic level, astrocytes form the “tripartite synapse”, where their processes enwrap synaptic terminals, modulating synaptic transmission and plasticity [7]. They respond dynamically to neuronal activity through various mechanisms such as calcium signaling or structural changes, which can regulate neurotransmitter levels via modulation of their clearance after release, thereby influencing synaptic strength. At the cellular level, astrocytes regulate homeostasis [8], ionic balance [9], and brain energy metabolism [10], which is critical for proper neuronal function. Moreover, astrocytes extend processes that interact with hundreds of dendrites and thousands of synapses [11], coordinating network-level activity and synchronizing large-scale neural circuits [12].

Recently, emerging evidence has shown that astrocytes directly contribute to shaping the CPs of plasticity in the brain. These cells influence the timing of synaptic remodeling and circuit stabilization, acting as key players in the regulation of plasticity during these crucial developmental windows. This review explores how astrocytes impact the CP of plasticity, focusing on their roles in synapse remodeling, underlying both structural and functional plasticity of synaptic circuits.

## Neuronal determinants for critical periods

Neuronal plasticity during CPs involves both structural and functional remodeling of synapses, as well as maturation of inhibitory circuits (See Reviews [13–15] and Figure 1). The primary visual cortex (V1) has long served as a model for uncovering mechanisms underlying CP plasticity due to its characteristic OD plasticity,
<figure><img src="image_5.png" /><figcaption>**Figure 1**</figcaption></figure>

**Neuronal circuits and extracellular matrix maturation: functional impact during CPs.** Illustration of the key mechanisms driving plasticity during CPs. Thalamocortical projections (bottom right) undergo structural remodeling through pruning and the formation of new connections in response to sensory experience. At excitatory synapses (left), dendritic spines on pyramidal neurons exhibit changes in density and motility. Silent synapses become functional with the insertion of AMPA receptors, while synaptic strength is further fine-tuned by the balance between long-term potentiation (LTP) and long-term depression (LTD). Parvalbumin-positive (PV) interneurons (top right) are crucial for maintaining the excitatory/inhibitory (E/I) balance. These inhibitory neurons are enwrapped by perineuronal nets (PNNs), which stabilize synapses and act as molecular brakes to limit further synaptic plasticity as CPs close. *Created in BioRender. ROUACH, N. (2025).*

first observed in cats in the pioneering work of Hubel and Wiesel [1]. OD refers to the stronger response of the visual cortex neurons to inputs from one eye than the other. OD plasticity occurs when this balance shifts, particularly following MD, where closing one eye during the CP leads to a strengthening of connections from the open eye and a weakening of those from the closed eye. One of the first mechanism identified to account for OD plasticity is the remodeling of thalamocortical projections in V1. These inputs are refined through the pruning of excess connections and the formation of new ones in response to sensory experience, ensuring that synapses associated with active inputs are preserved and

reinforced, while inactive synapses are selectively eliminated [16].

However, this process is relatively slow and does not fully account for the rapid changes in OD observed within a few days of MD [17]. To complement this, faster structural plasticity is concurrently initiated, primarily at the postsynaptic site, specifically along the apical dendrites of cortical pyramidal cells. There, dendritic spines indeed undergo rapid changes in motility and density during CPs [18,19]. Additionally, silent synapses, which lack AMPA receptors, become functional during that time, as the latter receptors are inserted in response to neuronal
activity, thereby enhancing synaptic efficacy [20,21]. Synaptic plasticity in the form of long-term potentiation contributes to the unsilencing of these immature synapses by driving the insertion of AMPA receptors. Conversely, long-term depression is thought to result in the pruning of inactive synapses [21].

Maturation of inhibitory circuits, especially involving parvalbumin-positive (PV) interneurons, is crucial for regulating the timing of CPs. These interneurons are essential for establishing the excitatory/inhibitory (E/I) balance [22]. Moreover, the formation of perineuronal nets (PNNs) around PV neurons stabilizes these inhibitory circuits and serves as a molecular brake, further limiting synaptic remodeling and plasticity as CPs close [23]. Numerous factors function as triggers or brakes to regulate the onset and closure of these windows [14]. For instance, brain-derived neurotrophic factor (BDNF) promotes the onset of plasticity by accelerating circuit maturation, while GABAergic inhibition initially triggers CP plasticity, and later acts as a brake terminating CPs [13].

# Astrocytes development, plasticity and implication in critical periods

## Postnatal development of astrocytes

Astrocytes develop postnatally in synchrony with the peak period of synaptogenesis in the cortex, positioning them as crucial regulators of this process [24]. As they mature, astrocytes extend fine processes that contact developing synapses and secrete key synaptogenic factors such as thrombospondins or glypicans [5], This coordinated development allows astrocytes to actively shape the formation and maturation of synaptic connections. During subsequent stages of postnatal development, astrocytes actively remodel the extracellular matrix [25] and contribute to synaptic pruning [26], two key processes controlling the CPs. Overall, astrocytes are active partners in the formation, maturation and remodeling of synaptic circuits throughout the progression of CPs.

Moreover, astrocytes from different brain regions, such as the cerebral cortex, hippocampus, midbrain, and cerebellum, exhibit distinct synaptogenic profiles and gene expression patterns [27]. These regional differences in astrocyte function suggest that astrocytes contribute to the region-specific timing of CPs, tailoring their support to the unique developmental needs of neural circuits in various brain areas.

## Experience-dependent plasticity of astrocytes during critical periods

### Changes in molecular profiles during visual and auditory critical periods

The development of single-nucleus RNA sequencing has provided insights into astroglial triggers and brakes that

could be involved in the opening and closure of the CP. By comparing gene expression in the primary auditory cortex (A1) of normal- and tone-reared mice during CP development, Kalish et al. [28] revealed altered expression of several hundred genes affecting not only neuronal, but also glial cells (Table 1). In particular, this study revealed that tone-rearing in mice leads to significant changes in astroglial gene expression, including the glutamate transporter *Slc1a3* (GLAST), the small conductance calcium-activated channel *Kcnm2* (SK2 channel), and the Hes Family BHLH Transcription Factor 5 (*Hes5*). Additionally, expression of several immediate-early genes, hallmarks of plasticity, were upregulated by tone rearing in A1 in astrocytes. These include the FBJ osteosarcoma oncogene *Fos*, the transcription factor *Junb*, and the Nuclear Receptor Sub-family *Nr4a1*.

These results are reminiscent of early work in V1, indicating that the expression of the immediate early genes *Fos*, *Junb* and *Nr4a1* is also modified following MD in V1 during the CP, with one main difference: they were downregulated by MD [29]. This latter study used bulk RNAseq, so it is unclear which cell type is involved in these regulations, possibly explaining this discrepancy. Moreover, the work of Madjan & Shatz [29] also revealed that the expression of several other genes is impacted by MD, some of which being likely attributable to astrocytes (Table 1). These genes include the Gap Junction Protein Alpha 1 (*Gja1*, encoding the connexin Cx43), the Insulin-like Growth Factor Binding Protein 2 (*Igfbp2*) and the Type 2 Deiodinase (*Dio2*), the latter activating the thyroid hormones, which have recently been proposed to regulate the CPs [30]. However, while developmental changes in gene expression are associated with CPs, causal manipulations are needed to definitely relate these genes to CPs.

### Structural and functional regulation of astrocytes by visual and social experience

Astrocytes also display experience-dependent plasticity at the structural and functional levels during CPs. In the visual cortex, dark-rearing indeed delays astrocytic maturation compared to mice raised with normal light exposure, particularly in cortical layers outside layer IV, as evidenced by the reduced expression of glial fibrillary acidic protein (GFAP) and the lower density of astrocytic processes [34]. In contrast, environmental enrichment, particularly when combined with physical exercise, increases the surface density of astrocytic processes [35], and counteracts the effects of dark-rearing, significantly increasing the density of astrocytes in the visual cortex [36].

Interestingly, beyond sensory experience, social stimuli can also induce structural and functional astrocytic plasticity in juvenile mice. Social deprivation indeed
<caption>**Table 1**</caption>

Differentially regulated astroglial genes during critical periods in mice auditory and visual cortices. This table summarizes key astrocytic genes that are differentially regulated during the CP of plasticity, suggesting their roles as potential triggers or brakes in regulating synaptic plasticity. The first column lists the gene names. The second column indicates whether the gene is up- or down-regulated compared to control conditions. The third column indicates the brain region (A1, primary auditory cortex. V1, primary visual cortex). The fourth specifies when the gene shows differential regulation (before, at the peak, or at the closure of the CP). The fifth column provides the full name of each gene, while the sixth column includes additional observations relevant to their role in astrocytic plasticity during the CP.

<table><thead><tr><th>Gene name</th><th>Up- or Down-regulation</th><th>Brain region</th><th>Pre/peak/ Post -CP</th><th>Description</th><th>Observation</th></tr></thead><tbody><tr><td>Slc1a3</td><td>Down</td><td>A1</td><td>Peak/Post</td><td>Solute carrier Family 1 Member 3</td><td></td></tr><tr><td>Kcnn2</td><td>Down</td><td>A1</td><td>Peak/Post</td><td>Potassium calcium-activated channel Subfamily N Member 2</td><td></td></tr><tr><td>Fos</td><td>Up</td><td>A1</td><td>Peak/Post</td><td>FBJ osteosarcoma oncogene</td><td></td></tr><tr><td>Junb</td><td>Up</td><td>A1</td><td>Peak/Post</td><td>Transcription factor</td><td></td></tr><tr><td>Nr4a1</td><td>Up</td><td>A1</td><td>Peak/Post</td><td>Nuclear receptor subfamily 4, group A, member 1</td><td></td></tr><tr><td>Dio2 (AF096875)</td><td>Down</td><td>V1</td><td>Post</td><td>Type 2 Deiodinase</td><td>Protein levels in astrocytes studied in [31]</td></tr><tr><td>Gja1 (M63801)</td><td>Down</td><td>V1</td><td>Post</td><td>Gap junction protein alpha 1</td><td>Protein levels in astrocytes studied in [32]</td></tr><tr><td>Igfbp2 (X81580)</td><td>Down</td><td>V1</td><td>Peak</td><td>Insulin-like growth factor binding protein 2</td><td>Protein levels in astrocytes studied in [33]</td></tr></tbody></table>

induces in hippocampal astrocytes cytoskeleton changes, with an upregulation of GFAP expression, and this effect is specific to juvenile mice as it is not observed in adults. Furthermore, social deprivation induces functionally calcium hyperactivity in hippocampal astrocytes from juveniles, which impairs cognitive functions like learning and memory [37]. This exacerbated calcium activity is regulated by TRPA1 signaling, and inhibiting this pathway in astrocytes mitigates the cognitive deficits caused by social deprivation. However, causal manipulations are needed to fully relate the changes in astroglial properties in juvenile mice to developmental CPs.

Altogether, this data indicates that astrocytes respond dynamically and are highly sensitive to environmental experiences in various systems, adjusting their functional and structural properties based on sensory, motor, social and emotional stimuli.

## Manipulating astrocytes modifies critical period plasticity

Studies have provided direct evidence that astrocytes are actively involved in regulating the temporal dynamics of CPs. For instance, transplantation of immature astrocytes in V1 restores OD plasticity in both cats [38] and mice [39]. In both species, cultured astrocytes from newborns were transplanted into the visual cortex of adults beyond their CP, and this manipulation successfully reinstated OD plasticity after MD. These

results underscore astrocytes' essential role in shaping CP plasticity, and point to conserved mechanisms across different species.

Similarly, disrupting astrocyte functions can impair both visual and cognitive CP plasticity. The inhibition of astrocytes metabolism with the fluorocitrate gliotoxin results in the suppression the MD-induced OD shift in the visual cortex of kittens [40], while when combined with monocular enucleation in adult mice, it impairs neuronal recovery and plasticity in V1 [41]. This underscores the crucial role of astroglial metabolism in modulating plastic changes after sensory loss. Additionally, genetic ablation of astrocytes in *Drosophila* using astroglial expression of a pro-apoptotic gene prolongs a recently identified developing motor circuit CP occurring during late embryogenesis. This CP involves activity-dependent changes in dendrite length, complexity and connectivity of motor neurons, demonstrating that astrocytes are essential for the timing of motor circuit CP closure [42].

Finally, in the developing hippocampus, enhancing astrocytes proliferation by overexpressing epidermal growth factor receptors (EGFRs) in astrocyte progenitors causes autistic-like behaviors in mice, increasing inhibitory synaptic transmission and disrupting excitation/inhibition balance [43], hence modifying fundamental mechanisms for both the establishment and closure of CPs.
**Astroglial basis of brain plasticity in critical periods: mechanistic insights**

**Remodeling of neuroglial circuits**

Astrocytes play a central role in regulating the shaping of neural circuits during CPs by controlling synapse formation, maturation, and elimination [5] (Figure 2a). One key astrocyte-secreted proteins involved in glutamatergic synapse formation is Hevin (SPARC-like 1), which facilitates the assembly of thalamocortical synapses by bridging neuroligin-1B and neurexin-1α [44]. The loss of

Hevin indeed impairs thalamocortical synapse formation, resulting in diminished synaptic connectivity and weakened sensory processing [45]. Experiments involving MD during the CP show that astrocyte-secreted Hevin is essential for assembling thalamocortical circuits that support experience-dependent plasticity [44].

In addition to synapse formation, astrocytes also regulate synaptic maturation via Chordin-like 1 (Chrdl1), another astrocyte-derived protein that limits plasticity by

<figure><img src="image_6.png" /><figcaption>**Figure 2**</figcaption></figure>

**Astroglial mechanisms of synaptic and structural plasticity during critical periods.** (a) Synapse formation, maturation, and elimination. Astrocytes are pivotal in synapse formation by secreting proteins like Hevin, which facilitates the assembly of thalamocortical synapses. They also regulate synaptic maturation through proteins such as Chordin-like 1 (Chrdl1), which promotes synaptic stability by facilitating the insertion of GluA2-containing AMPA receptors. Astrocytes also mediate synapse elimination via phagocytic receptors MEGF10 and MERTK. (b) Extracellular Matrix Formation and Degradation: Astrocytes control the composition and remodeling of the extracellular matrix, including the regulation of chondroitin sulfate proteoglycans (CSPGs). They also facilitate extracellular matrix degradation through matrix metalloproteinase 9 (MMP-9), which is regulated by astrocytic connexin 30 (Cx30) via the RhoA-ROCK signaling pathway. (c) Microtubule stability. Astrocytes influence the structural stability of neuronal circuits by modulating microtubule dynamics within dendrites. (d) ATP-Adenosine Release and Synaptic Modulation. Astrocytes modulate synaptic efficacy through the release of ATP, which is subsequently converted into adenosine. This process activates A1 adenosine receptors, leading to long-term depression (LTD) of synaptic activity. (e) Glutamate Uptake and Synaptic Refinement. Astrocytes regulate synaptic refinement during CPs by regulating glutamate levels through transporters like GLT1. Created in BioRender. ROUACH, N. (2025).
promoting the insertion of GluA2-containing AMPA receptors into synapses [46]. This mechanism stabilizes synaptic connections, promoting CP closure by impairing synaptic remodeling. Without Chrdl1, synapses in the visual cortex exhibit reduced GluA2 expression, indicative of immature synapses. Monocular enucleation during the CP induces greater synaptic remodeling in Chrdl1 knockout mice, reflecting enhanced plasticity in the absence of Chrdl1. This heightened plasticity persists into adulthood, demonstrating that Chrdl1 limits plasticity in both the developing and adult V1 [46].

Finally, astrocytes participate in synapse elimination. Astrocytes use phagocytic receptors, such as MEGF10 and MERTK, to remove inactive synapses, promoting optimal circuit function [26]. In the visual system, astrocyte-specific knockouts of MEGF10 and MERTK exhibit an excess of unpruned synapses, disrupting the normal refinement of retinogeniculate projections. This astrocyte-mediated synapse elimination is driven by retinal activity, as demonstrated by the use of epibatidine, a retinal wave-blocking drug [26], and may directly contribute to the CPs dynamics. CP plasticity indeed relies on experience-dependent synaptic remodeling, particularly in the refinement of thalamocortical projections (See Figure 1). During OD plasticity in V1, thalamocortical synapses from the deprived eye are eliminated while those from the open eye are formed. Given their established role in synaptic pruning, astrocytes may thus actively participate in this refinement by selectively removing deprived thalamocortical synapses, thereby shaping CP dynamics. Future studies should confirm this experimentally and identify the molecular mechanisms driving this process.

## Coordinated cellular and extracellular structural plasticity

A key process through which astrocytes control the CP is the modulation of chondroitin sulfate proteoglycans (CSPGs), components of PNNs (Figure 2b). The CSPGs play a pivotal role in regulating the duration of plasticity during CPs [47]. Astrocytes can regulate the expression of various CSPGs during nervous system development [25]. As a result, astrocytes could regulate the formation of PV cells PNNs, hence shaping the CP.

Astrocytes are also involved in ECM degradation, particularly through the release of matrix metalloproteinase 9 (MMP-9), which facilitates the breakdown of CSPGs, thereby loosening PNNs and facilitating synaptic remodeling during development. Coherently, this degradation is crucial for reopening plasticity windows in the adult brain [23]. Recent work has shown that astrocytic control of MMP-9 levels, regulated through a newly identified Cx30-RhoA-ROCK signaling pathway, leads to the degradation of PNNs (Figure 2b) [39]. Downregulation of Cx30 in astrocytes,

an astroglial gap junction protein, increases MMP-9 expression and induces a protracted and enhanced plasticity in V1 after MD. This recent work further highlights the crucial role of astrocytes in coordinating ECM remodeling and inhibitory circuits maturation during CPs.

## Functional regulation of synaptic circuits during critical periods

### Via changes in structural properties

Astrocytes actively regulate the structural dynamics of neurons, notably through the neuroligin-neurexin signaling pathway, which plays a critical role in the development of dendritic microtubules and synaptic structures (Figure 2c). In *Drosophila* motor circuits, in addition to genes related to the excitatory-inhibitory balance and synthesis of CSPGs, a recent study revealed that astrocytic neuroligin is required for the closure of the CP [42]. This cell adhesion protein binds to motor neurons’ neurexins to promote microtubule stability. These findings indicate that astrocyte-driven changes in neuronal structural properties are key to the timing and regulation of CPs.

### Via changes in synaptic efficacy

Astrocytes also influence synaptic efficacy by modulating neurotransmitter availability and receptor activation. In the hippocampus, astrocytic release of ATP, which is subsequently converted into adenosine via extracellular ectonucleotidases, has been shown to play a crucial role in long-term depression (LTD) through A1 adenosine receptor activation [48] (Figure 2d). This process contributes to the developmental loss of spike timing-dependent depression during CPs, as demonstrated by the impaired LTD of developing synapses by the blockade of adenosine receptors. Conversely, astrocytes regulate synaptic refinement through the uptake of glutamate, which coordinates eye-specific responses in the visual cortex during the CP [49] (Figure 2e). Deficiency for astrocytic glutamate transporters GLT1 leads to impairment in synaptic refinement, highlighting the importance of astrocytes in maintaining synaptic efficacy and refining neural circuits based on experience-dependent inputs.

Astrocytes further regulate synaptic plasticity during CPs through the release of cytokines like tumor necrosis factor-alpha (TNF-α). TNF-α has been implicated in controlling homeostatic plasticity by adjusting synaptic strength to maintain circuit stability in response to prolonged changes in sensory inputs [8]. During the visual cortex CP, astrocytic TNF-α release is indeed regulated by sensory experience [50], which induces homeostatic changes in synaptic scaling to compensate for the loss of inputs. Homeostatic plasticity-induced release of astrocytic TNF-α may thus shape cortical circuit refinement during CPs.
## Concluding remarks and perspectives

Recent studies now establish astrocytes as active regulators of CP plasticity, shaping the timing and extent of neural plasticity in the developing brain. By controlling synapse formation, maturation and elimination, astrocytes fine-tune neural circuits in response to sensory inputs, as particularly demonstrated in the visual cortex. Their ability to regulate the extracellular matrix, including the formation and degradation of perineuronal nets contributing to the maturation of inhibitory circuits, further highlights their role in stabilizing neural connections as CPs close.

While the current body of work focuses largely on the visual cortex, these astrocytic mechanisms may extend to other sensory, motor, and cognitive systems. Future studies could explore how astrocytes contribute to CPs in diverse neural circuits, providing broader insights into the brain's capacity for plasticity. Additionally, findings across species such as mice, cats, and even invertebrates suggest that some astrocytic roles in plasticity may be evolutionarily conserved, but more work is needed to confirm this across different brain systems and organisms.

The therapeutic potential of targeting astrocytic functions to reopen plasticity in the adult brain is an exciting prospect. Whether for recovery after neural injury or for addressing neurodevelopmental disorders, astrocytes offer a promising avenue for therapeutic interventions aimed at restoring or extending CPs of plasticity. Further research into astrocyte-mediated regulations will undoubtedly shed new light on the brain's remarkable capacity for adaptation.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgements

This work was supported by grants from the European Research Council (consolidator grant no. 683154), ANR (MicroSenso, ANR-19-CE16-0018 and SensoPAP, ANR-24-CHBS-0007), and Fondation pour la Recherche Médicale (Rachel Ajzen et Léon Iagolnitzer Prize) to N. R. *Figures were created with BioRender (license granted to ROUACH, N.)*

## Data availability

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

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emphasizing the importance of astrocytic glutamate regulation in synaptic pruning and visual circuit refinement.

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