Glial Control of Cortical Neuronal Circuit Maturation and Plasticity

Abstract

The brain is a highly adaptable organ that is molded by experience throughout life. Although the field of neuroscience has historically focused on intrinsic neuronal mechanisms of plasticity, there is growing evidence that multiple glial populations regulate the timing and extent of neuronal plasticity, particularly over the course of development. This review highlights recent discoveries on the role of glial cells in the establishment of cortical circuits and the regulation of experience-dependent neuronal plasticity during critical periods of neurodevelopment. These studies provide strong evidence that neuronal circuit maturation and plasticity are non-cell autonomous processes that require both glial–neuronal and glial–glial cross talk to proceed. We conclude by discussing open questions that will continue to guide research in this nascent field.

Introduction

The complex architecture of the mature brain is achieved through activity-dependent remodeling of brain circuitry, which is enhanced during specific “critical periods” of development (Katz and Shatz, 1996; Hua and Smith, 2004; Holtmaat and Svoboda, 2009). “Critical periods” or “critical windows” were first described over a century ago (Stockard, 1921) as particular times when biological systems display heightened sensitivity to experience. A key feature of critical periods is that structural changes become consolidated and are essentially irreversible, representing a more extreme version of “sensitive periods” for systems in which plasticity is transiently increased but is retained into adulthood (Hensch, 2004; Knudsen, 2004).

There is a large diversity of critical periods across brain development. Within a given brain region, there often exist multiple, successive critical periods for each stage of development, the timing of which differs between brain regions (Dow-Edwards et al., 2019; Reh et al., 2020). A well-studied example is ocular dominance plasticity (ODP; Wiesel and Hubel, 1963; Gordon and Stryker, 1996; B-S. Wang et al., 2010), in which loss of visual stimulus to one eye (i.e., monocular deprivation) leads to reduced responses to visual inputs from that eye even after vision is restored. ODP peaks during the critical period, ∼4 weeks of age in rodents, and decreases significantly in adulthood (Lehmann and Löwel, 2008). Similar types of critical periods for other sensory modalities and higher-order brain areas have also been described (Hensch, 2005; Erzurumlu and Gaspar, 2012; Persic et al., 2020).

Critical periods represent an important therapeutic target, offering potential for intervention in neurodevelopmental disorders such as autism spectrum disorder and schizophrenia (LeBlanc and Fagiolini, 2011; Ben-Ari, 2015; Exposito-Alonso and Rico, 2022) or improved recovery after traumatic brain and spinal cord injuries (Soleman et al., 2013; Nahmani and Turrigiano, 2014; Sánchez-Ventura et al., 2022). Indeed, there is evidence that critical periods can be reinstated in mature circuits by targeting mechanisms involved in critical period closure (Hensch, 2005; Marín, 2016; Heimler and Amedi, 2020), offering a therapeutic window for treatment.

The molecular mechanisms underlying critical periods include neuron-intrinsic factors as well as neuron-glia interactions (Starkey et al., 2023). Glial cells are the non-neuronal cells of the brain, including astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). Together, they make up roughly half of the cells in the human brain (von Bartheld et al., 2016). While recognizing the vast literature on neuron-intrinsic mechanisms, which has been extensively reviewed previously (Hensch, 2005; Hooks and Chen, 2007; Erzurumlu and Gaspar, 2012), this review will focus specifically on mechanisms involving glial cells. We discuss the role of glial cells both in the establishment of neural circuits during critical periods and in the timing of critical periods in the brain. We further highlight several recent studies that provide new insight into this emerging area of research.

Glial Control of Synapse Dynamics in Cortical Development

Astrocytes

The precise formation of synaptic connections is essential for proper establishment of neuronal circuits and cognitive function throughout life (Batool et al., 2019). In the rodent cortex, synapses form during the first postnatal month starting at Postnatal Days (P) 5–7, mature at P14, undergo pruning, and stabilize toward P28 (Farhy-Tselnicker and Allen, 2018; Farhy-Tselnicker et al., 2021). Cortical synaptogenesis is shaped by numerous mechanisms (Cohen-Cory, 2002; Andreae and Burrone, 2018), including sensory experiences such as the onset of patterned vision after eye-opening or whisker stimulation (Colonnese et al., 2010; Tatti et al., 2017; van der Bourg et al., 2017); changes in neuronal activity (Hooks and Chen, 2007; Espinosa and Stryker, 2012; Ackman et al., 2014; Ishikawa et al., 2014; Babij and De Marco Garcia, 2016); and regulation by non-neuronal cells including astrocytes, which together with neurons form the tripartite synapse (Araque et al., 1999; Allen and Eroglu, 2017; Farhy-Tselnicker and Allen, 2018).

Although neurogenesis precedes astrogenesis, synapses form only after astrocytes are generated, and the peak in synapse maturation at ∼P14 coincides with a peak in astrocytic morphogenic and transcriptomic changes (Bushong et al., 2004; Stogsdill et al., 2017; Farhy-Tselnicker et al., 2021). Both inhibitory and excitatory neuronal activity (Morel et al., 2014; Farhy-Tselnicker et al., 2021; Cheng et al., 2023), as well as sensory experiences such as dark rearing (Müller, 1990; Majdan and Shatz, 2006; Stogsdill et al., 2017), can impact astrocyte maturation, thus influencing their ability to regulate synapses. For example, recent work has shown that visually evoked neuronal activity regulates astrocytic expression of synapse-regulating genes Glypican 4 (Gpc4), which promotes synapse formation by regulating AMPA receptor (AMPAR) subunit GluA1 (Allen et al., 2012; Farhy-Tselnicker et al., 2017), and Chordin like 1 (Chrdl1), which promotes synapse maturation by upregulating GluA2 AMPAR levels (Blanco-Suarez et al., 2018). Mice lacking glutamate release from thalamocortical projections due to knock-out of vesicular glutamate transporter (VGluT) 2 have increased mRNA levels of Gpc4 and decreased levels of Chrdl1 at P14 compared with wild-type controls (Farhy-Tselnicker et al., 2021). Moreover, VGluT2 knock-out mice exhibit increased GluA1 and reduced GluA2 protein levels at P14, suggesting delayed synapse maturation (Farhy-Tselnicker et al., 2021). Similarly, inhibitory neuronal activity promotes astrocyte morphogenesis through astrocytic GABAB receptor (GABABR)-mediated pathways (Cheng et al., 2023). Deletion of astrocytic GABABR results in decreased astrocytic morphological complexity and deficits in neuronal circuit function (Cheng et al., 2023). Taken together, these findings strongly suggest that astrocytes engage in bidirectional cross talk with neurons to ensure proper synapse formation; however, the molecular mechanisms underlying these processes are not yet fully understood.

A central mediator of astrocytic responses to neuronal activity or sensory inputs is intracellular calcium levels. Astrocytic calcium signals are highly complex, exhibiting age, brain region, and neuronal activity state-specific responses (Shigetomi et al., 2016; Chai et al., 2017; Adamsky et al., 2018; Lines et al., 2020; Kellner et al., 2021; Cahill et al., 2024), and blocking astrocytic calcium signals adversely affects neuronal circuit function and behavior (Srinivasan et al., 2016; Yu et al., 2018). One cellular pathway by which astrocytic calcium is elevated is through G-protein–coupled receptor–inositol triphosphate (IP₃)-mediated release of calcium from endoplasmic reticulum (ER) stores (Mariotti et al., 2016; Sherwood et al., 2017; Guillot de Suduiraut et al., 2021). Mice lacking the astrocytic ER IP₃ receptor Type 2 (IP3R2 KO) exhibit deficits in behaviors such as impaired sleep state transitions (Vaidyanathan et al., 2021), social interaction deficits and repetitive behaviors (Q. Wang et al., 2021), as well as abnormal functional connectivity as measured by resting-state functional magnetic resonance imaging (J. Liu et al., 2022; Shah et al., 2022) and deficient serotonin-driven synaptic plasticity (González-Arias et al., 2023). Notably, no differences are observed in anxiety levels, locomotor activity, and spatial navigation in IP3R2 KO mice (Petravicz et al., 2014; Q. Wang et al., 2021), further highlighting the context-dependent roles of astrocytic calcium signals. Collectively, these studies demonstrate the importance of astrocytic calcium activity for normal brain function. However, the relationship between astrocytic store-released calcium and astrocytic synapse regulation, particularly during development, remains unresolved.

In addition to being regulated by neuronal activity, the developmental expression patterns of astrocytic synapse-regulating genes (e.g., Gpc4, Chrdl1) and AMPAR subunits are both regulated by astrocytic store-released calcium and are altered in the visual cortex of IP3R2 KO mice (Farhy-Tselnicker et al., 2021). These mice also exhibit decreased levels of the presynaptic vesicular glutamate transporters VGlut1 and VGlut2 at P14 (Farhy-Tselnicker et al., 2021). These findings suggest a potential role of astrocytic store-released calcium in modulating excitatory synaptic transmission, which has important implications for circuit function and behavior. Future work will be needed to understand how neuronal activity is altered in IP3R2 KO mice and whether astrocyte morphogenesis may be an underlying mechanism.

To conclude, calcium dynamics are the hallmark of astrocyte activity (Shigetomi et al., 2016), yet the specific functions that these signals convey to mediate astrocyte responses are just beginning to be unraveled. Understanding how astrocytic store-released calcium signaling is linked to synapse formation and subsequent circuit function will elucidate the intricate relationship between neurons and astrocytes during normal development, providing important insight into how these interactions may be altered in disease.

Microglia

Microglia enter the brain at embryonic timepoints before the emergence of astrocytes and OPCs, and unlike astrocytes and OPCs, which are derived from neuroectoderm, microglia are tissue-resident macrophages derived from the embryonic yolk sac (Ginhoux et al., 2010). As the only cells in the brain parenchyma with immune origin, microglia have many immune functions and signaling pathways relevant for host defense that get “repurposed” to ensure proper brain development (Paolicelli et al., 2022). Indeed, there are now many studies demonstrating microglial influence on cortical circuit formation and refinement through both nonphagocytic and phagocytic mechanisms (Faust et al., 2021).

Nonphagocytic mechanisms of synaptic refinement by microglia most often involve the release of soluble factors that modulate circuit function. One such example is microglial brain-derived neurotrophic factor (BDNF), which induces spine formation and plasticity in motor cortex neurons during motor learning (Parkhurst et al., 2013). Microglia can also induce synapse formation via process contact with dendritic segments (Miyamoto et al., 2016) in the somatosensory cortex. In the retinogeniculate pathway, FN14 is upregulated on postsynaptic neurons during sensory experience and induces the expression of its ligand TWEAK (TNF-associated weak inducer of apoptosis) in microglia, decreasing spine numbers through a nonphagocytic mechanism (Cheadle et al., 2020). There are also studies demonstrating that microglial TNFα impacts synaptic transmission. For example, microglial TNFα suppresses glutamatergic synaptic strength in the nucleus accumbens and modulates behavioral sensitization to cocaine (Lewitus et al., 2016), and elevated TNFα levels caused by IRF8 loss in microglia lead to increased circuit instability and seizure susceptibility (Feinberg et al., 2022). Finally, microglia can directly detect, respond to, and control neuronal activity in the striatum via ATP and P2YR12 signaling (Badimon et al., 2020).

Microglia can also modulate synapse dynamics in the developing brain through activity-dependent phagocytosis of synaptic elements (Tremblay et al., 2010; Paolicelli et al., 2011; Schafer et al., 2012). Molecular studies, largely performed in transgenic knock-out mice, suggest that engulfment of synapses by microglia is mediated by “find me,” “eat me,” and “don't eat me” signaling pathways shared with the immune system. “Eat me” pathways include the complement system proteins C1q and C3 (Schafer et al., 2012), externalized phosphatidylserine (Scott-Hewitt et al., 2020), CX3CR1/CX3CL1 (Paolicelli et al., 2011; Gunner et al., 2019), IL-33 (Vainchtein et al., 2018; Nguyen et al., 2020; Han et al., 2022), TREM2 (Filipello et al., 2018), and CSF1 (Wohleb et al., 2018). In addition, ATP-P2YR12 is a “find me” pathway that has also been implicated in synapse elimination by microglia (Sipe et al., 2016). In contrast, the SIRPα/CD47 (Toth et al., 2013; Lehrman et al., 2018; Jiang et al., 2022) pathway is the only currently identified “don't eat me” pathway that regulates microglia-synapse interactions in the developing brain. A recent study suggests that astrocyte–synapse contact may be another such “don't eat me” contextual cue (Faust et al., 2024), though a specific molecular mechanism has not yet been identified. Important work remains to determine why each specific phagocytic mechanism is only used in certain contexts, when synapse removal is mediated by microglia versus astrocytes or OPCs, how these mechanisms interact with neuron-intrinsic mechanisms of synapse elimination, and how to precisely distinguish active forms of synaptic pruning versus inactive “debris clearance.”

The realization that there is not one universal signal that controls microglial synapse refinement in the brain came with the identification of these cues (“eat me” and/or “don't eat me” signals) that guide microglia to phagocytose-specific synapses. Instead, there appear to be context-specific signals that tag specific subsets of synapses for phagocytosis (or protection) by microglia in specific brain regions. A recent study suggests, however, that there may be a more general “don't eat me” signal that programs microglia to a less “synapse-hungry” state once cortical circuits have matured (Devlin et al., 2024). The existence of such a signal would prevent developmentally inappropriate overeating of synapses. The neuron-derived cytokine interleukin-34 (IL34) is a recently identified “don't eat me” signal that, likely at a more circuit-wide level than SIRPα/CD47, puts the brakes on microglial pruning of thalamocortical synapses in the developing anterior cingulate cortex (ACC; Devlin et al., 2024). IL34 is upregulated in cortical neurons and is increased by neuronal activity. Disruptions in IL34 signaling result in microglial overengulfment of synapses, while overexpression of IL34 before the critical window prevents necessary synaptic engulfment (Devlin et al., 2024). These data support the hypothesis that IL34 expression in neurons programs microglia toward a more mature, homeostatic, and neuroprotective state that maintains healthy, active synapses.

OPCs

OPCs are the progenitor pool for myelinating oligodendrocytes that are maintained from development and throughout adulthood. OPCs are distinct among other glial cell types as they receive direct synaptic innervation from neurons (Bergles et al., 2000) and express a plethora of postsynaptic proteins, including postsynaptic adhesion molecules and neurotransmitter receptors (Spitzer et al., 2019). Due to their expression and maintenance of these synaptic proteins and structures, OPCs can respond to synaptic activity via both the modulation of their membrane potential (Bergles et al., 2000) and through internal calcium signaling (Fiore et al., 2023; Lu et al., 2023; Li et al., 2024). Moreover, synaptic activity can influence OPC differentiation into myelinating oligodendrocytes. For example, stimulation of afferents via optogenetics (Gibson et al., 2014), forced motor tasks (Osso et al., 2021), or chemogenetic stimulation of calcium responses in OPCs themselves (Fiore et al., 2023; Li et al., 2024) can all increase de novo myelination of axonal fibers through OPC to oligodendrocyte differentiation. Furthermore, synaptic activity on OPCs predicts placement of myelin sheaths in zebrafish (Li et al., 2024). Therefore, neurons can stimulate the production of myelinating oligodendrocytes and downstream de novo myelination of axonal fibers via OPC responses to synaptic activity, and OPCs can then, in turn, affect signal transmission and plasticity (Li et al., 2024).

In addition to their capacity to influence myelination and thus axonal conductance and plasticity, the ability of OPCs to respond to the synaptic environment makes them promising candidates to participate in circuit development and modulation outside of oligodendrocyte production. In line with this, recent work has revealed that OPCs have noncanonical roles in coordinating neuronal circuit maturation. For example, OPCs are required for normal innervation and arborization of retinal ganglion cell (RGC) axons in the zebrafish optic tectum, a region populated by OPCs but largely devoid of oligodendrocytes (Xiao et al., 2022). Specifically, ablation of OPCs during the initial innervation of the optic tectum by RGCs [2 d post fertilization (dpf)] causes increased and inaccurate innervation patterns. Furthermore, ablation of OPCs after initial innervation has been established (7 dpf) decreases RGC remodeling and impairs behavioral responses to visual inputs, suggesting that OPCs aid in coordinating visual circuit development and maintenance (Xiao et al., 2022).

In agreement with data from zebrafish, OPCs in the mouse primary visual cortex can modulate thalamocortical innervation and potentially other synapses (Auguste et al., 2022; Buchanan et al., 2022). OPCs engulf neuronal axons and synaptic inputs in the primary visual cortex, which then get shuttled into phagolysosomes (Auguste et al., 2022; Buchanan et al., 2022). Furthermore, OPCs increase their engulfment of synapses during sensory experience-dependent synaptic refinement, a period of heightened plasticity that occurs from P20 to P30 (Auguste et al., 2022). Intriguingly, OPCs’ increased engulfment of synapses required the presence of microglia, suggesting that glial–glial cross talk may coordinate downstream OPC-mediated modulation of visual neural circuits. The phagocytic capacity of OPCs may also be preserved in humans, as human-induced OPCs are capable of engulfing synaptosomes as well as presynaptic inputs in an organoid model of fetal development (Gkogka et al., 2023). Taken together, these results demonstrate that OPCs can participate in the refinement of neural circuits through the modulation of axonal arborization, as well as through the phagocytosis of axonal and synaptic structures.

Glial Control of Critical Periods for Experience-Dependent Neuronal Plasticity

Astrocytes

Astrocyte maturation and function are critical for the proper wiring of neural circuits. Recent evidence has shown that astrocyte signaling drives critical period closure in multiple developing circuits (Ackerman et al., 2021; Ribot et al., 2021; Martínez-Gallego et al., 2022). In the developing Drosophila motor circuit, motor neurons exhibit heightened activity-dependent remodeling during late embryogenesis. Throughout the critical period, astrocytic neuroligins interact with neuronal neurexins to stabilize dendritic microtubules and reduce dendritic plasticity (Ackerman et al., 2021). Knockdown of Neurexin 1 (Nrx1) and Neuroligin 2 (Nlg2) extends a motor critical period, while overexpression precociously closes it. These findings demonstrate that Nlg2-Nrx1 signaling regulates critical period timing and that disruptions in Nlg2 and Nrx1 expression lead to lasting activity-dependent changes in motor circuit architecture, dendrite plasticity, and motor function.

Astrocytes also contribute to experience-dependent plasticity during visual system development (Ribot et al., 2021). Transplantation of immature astrocytes into the mature visual cortex enhances ODP, indicating that mature and immature astrocytes have distinct plasticity-promoting or restricting properties (Ribot et al., 2021). Indeed, knockdown of astrocytic connexin 30, which normally is upregulated in mature astrocytes, recapitulates the effect of immature astrocyte transplantation into the adult brain. Through atypical signaling, connexin 30 downregulates the RhoA-matrix metalloproteinase 9 pathway, leading to reduced levels of extracellular matrix (ECM)-degrading enzyme MMP9, maturation of perineuronal nets (PNNs) around inhibitory neurons, and critical period closure.

In addition to studies demonstrating the role of astrocytes in functionally closing critical periods, astrocyte signaling has also been implicated in developmental changes in spike timing-dependent plasticity (Martínez-Gallego et al., 2022). In the somatosensory cortex of mice, astrocytic release of adenosine promotes the transition from spike timing-dependent long–term depression to long-term potentiation (LTP). This astrocyte-mediated transition to LTP is believed to mark the end of synaptic plasticity in the somatosensory cortex.

Astrocytes may use a core set of mechanisms to close critical periods across distinct circuit types. In the visual cortex, critical period timing is regulated by astrocytic modulation of ECM degradation (Ribot et al., 2021). Interestingly, astrocyte-derived ECM cues are also essential for closure of the Drosophila motor critical period (Ackerman et al., 2021). These findings demonstrate that astrocytes are highly involved in critical period closure and play an important role in regulating activity-dependent changes in neural circuit plasticity across multiple brain regions.

Microglia

Although it is generally accepted that microglia regulate the formation and refinement of synaptic circuits during critical windows of development, an explicit role of microglia in the timing and closure of developmental critical windows has not been extensively explored. However, microglia regulate a number of cellular/molecular substrates strongly linked to the closure of critical periods.

One important substrate involved in the timing of critical periods is the ECM and, in particular, the establishment of PNNs (Fawcett et al., 2019; Reh et al., 2020; Carulli and Verhaagen, 2021). Multiple studies have demonstrated that removal of PNNs and/or their components is sufficient to reopen critical windows (Pizzorusso et al., 2002; Lensjø et al., 2017; Rowlands et al., 2018; Boggio et al., 2019). Emerging evidence suggests that microglia are key regulators of ECM composition. Mice that undergo microglial depletion by CSF1R inhibitors have increased numbers of PNNs in the cortex and hippocampus, which recover with adult microglial repopulation (Strackeljan et al., 2021; Y-J. Liu et al., 2021). In addition, in models of Huntington's disease (Crapser et al., 2020a), Alzheimer's disease (Crapser et al., 2020b), and CSF1R-related leukoencephalopathy (Arreola et al., 2021), depletion of microglia prevents loss of PNNs in the brain. Microglial remodeling of ECM can occur both through the secretion of MMPs that degrade ECM and direct phagocytosis of ECM components. In conditions of inflammation, microglia increase expression of MMPs (Könnecke and Bechmann, 2013), and inverse correlations have been observed in vivo between expression levels of microglial MMPs and the density of PNNs (Pantazopoulos et al., 2020). In other circumstances, both upregulation of MMPs and microglial engulfment of ECM have been observed. For example, repeated ketamine administration and 60 Hz light stimulation induce both upregulation of MMP9 in microglia and engulfment of ECM, leading to loss of PNNs in the cortex (Venturino et al., 2021). Microglia also phagocytose ECM in the spinal cord after spinal nerve injury, leading to degradation of PNNs which promotes pain (Tansley et al., 2022). In addition to removal of PNNs surrounding cell bodies, microglia engulf ECM surrounding synapses in the adult hippocampus, which facilitates spine plasticity and memory consolidation (Nguyen et al., 2020). Of note, this form of ECM engulfment is induced by IL-33 secreted by astrocytes, which implicates astrocyte–microglial cross talk in this process.

Another potential role of microglia in regulating the timing of critical windows is via signaling to astrocytes during development (Faust et al., 2024). In the neonate somatosensory cortex, sensory deprivation via whisker lesioning induces microglia to release Wnts, which activate Wnt signaling in astrocytes and reduces astrocyte–synapse contact. This microglia–astrocyte Wnt cross talk is required for activity-dependent synapse remodeling in the somatosensory cortex, which involves engulfment and removal of synapses by microglia. Given the role of astrocyte–synapse interactions in regulating critical period closure, these findings suggest the intriguing possibility that microglia could regulate the timing of critical windows of plasticity through molecular cross talk with astrocytes.

Oligodendrocytes and myelin

The concept of myelination acting as a brake on neuronal plasticity has been around for a long time (Hensch, 2005). The region-specific timing of developmental oligodendrogenesis and myelination tracks closely with a period of circuit refinement and synaptic pruning in those regions (Dow-Edwards et al., 2019). In addition, molecules enriched in myelin sheaths are frequently inhibitory for neurite outgrowth in the context of injury and neuronal regeneration (Geoffroy and Zheng, 2014). The membrane protein Nogo is one such example, being enriched in myelin sheaths, functionally inhibitory for axon regeneration following central nervous system injury (Schwab, 2010), and capable of influencing dendritic and synaptic morphology (Zemmar et al., 2018). An early study reported that global knock-out of Nogo or its receptors in mice leads to the persistence of critical period-like plasticity in the adult visual cortex (McGee et al., 2005). Specifically, in these global knock-out mice, a brief period of monocular deprivation is sufficient to cause a shift in ocular dominance of visual cortex neurons from the contralateral deprived eye to the ipsilateral nondeprived eye—a functional adaptation that is prominent during the critical period but much more limited in the adult cortex of control animals (Gordon and Stryker, 1996). This seminal observation raised the intriguing possibility that progression of myelination during development may functionally terminate the critical period for ODP, as an increase in myelin sheaths in the visual cortex would also increase the abundance of Nogo. However, given that all major cell types in the brain express both Nogo and its receptor (Zhang et al., 2014), it is unclear from this study whether the effects of Nogo deletion can be attributed to oligodendrocytes and/or myelin itself. Furthermore, Nogo is only one of many molecules enriched in myelin that could signal to other cell types in the developing circuit (Xin and Chan, 2020).

To directly test the role of oligodendrocyte maturation and myelination in regulating visual cortex plasticity, a recent study halted the progression of oligodendrogenesis and myelination during the critical period by conditionally deleting Myrf, a transcription factor required for oligodendrocyte differentiation and myelination (Emery et al., 2009), from OPCs (Myrf cKO; Xin et al., 2024). Mice lacking adolescent oligodendrogenesis exhibit a sparse, patchy pattern of myelination and significantly reduced visually evoked responses in the adult visual cortex. Following monocular deprivation, adult control mice maintain stable visual cortex responses to the deprived eye, whereas adult Myrf cKO mice exhibit a significant reduction in deprived eye responses, reminiscent of the functional plasticity typically restricted to the critical period (Sawtell et al., 2003). At the cellular level, adult Myrf cKO mice have fewer dendritic spines and greater spine turnover in visual cortex pyramidal neurons, indicating a baseline level of enhanced structural plasticity. Monocular deprivation induces spatially coordinated decreases in the spine size in Myrf cKO, but not control, mice, providing a potential structural basis for the reduction in functional visual cortex responses observed only in Myrf cKO mice.

At the circuit level, oligodendrocytes myelinate both excitatory neurons and, crucially, a large percentage of parvalbumin-expressing interneurons in the visual cortex (Micheva et al., 2016). Maturation of inhibition is essential for visual cortex critical period opening and closure (Fagiolini and Hensch, 2000; Hensch, 2005). Although parvalbumin neuron density is unaltered in Myrf cKO mice, inhibitory synaptic transmission is strongly reduced (Xin et al., 2024). Thus, disrupted inhibitory transmission may be the circuit basis for enhanced plasticity in the absence of adolescent oligodendrogenesis and myelination. Altogether, these results demonstrate a critical role for oligodendrocytes and myelin in regulating both structural and functional neuronal plasticity within the mammalian cortex. Follow-up studies will elucidate the extent to which this increase in experience-dependent plasticity impacts other cortical regions and related behaviors.

Conclusion

Recent work has uncovered multifaceted roles of all major glial cell types in regulating both the maturation and plasticity of neuronal circuits. There is ample evidence that astrocytes and microglia participate in the formation, maturation, and pruning of synapses (Bosworth and Allen, 2017; Farhy-Tselnicker et al., 2017, 2021; Blanco-Suarez et al., 2018) over the course of development, and emerging work is beginning to implicate OPCs (Auguste et al., 2022; Buchanan et al., 2022) and oligodendrocytes (Zemmar et al., 2018; Xin et al., 2024) in synapse stabilization and pruning as well (Fig. 1). Beyond the synapse, dendrite and axon arborization are also regulated by astrocytes (Ackerman et al., 2021), oligodendrocytes (Zemmar et al., 2018), and OPCs (Xiao et al., 2022). Taken together, these studies clearly demonstrate that proper circuit maturation is a non-cell autonomous process that requires not only glial–neuronal cross talk but also glial–glial cross talk.

Figure 1.

Glial control of synapse dynamics in cortical development. Schematic of a subset of synapse-related glia–neuron interactions that occur during cortical circuit maturation. Astrocytes release various signaling molecules to regulate synapse formation and maturation [e.g., expression of pre- and postsynaptic elements like VGluTs and ionotropic glutamate receptors (AMPARs)], which require elevations in astrocyte intracellular calcium (Ca²⁺) gated by the ER-associated calcium channel IP₃R2 (see main text for additional examples). Microglia interact with pre- and postsynaptic elements to promote synapse formation/removal, via engulfment of synaptic material as well as release of various soluble signaling molecules (e.g., BDNF). Microglia also respond to cues released by neurons that regulate the extent of engulfment (e.g., IL34). OPCs can regulate axon arborization and engulf presynaptic elements, the extent to which is regulated by the presence of microglia.

Intriguingly, the extent to which these cellular interactions occur frequently appears to be modulated by external experiences and/or neuronal activity (Gunner et al., 2019; Auguste et al., 2022; Block et al., 2022; Devlin et al., 2024). Therefore, it is not entirely surprising that glial cells play crucial roles in either permitting or restricting experience-dependent neuronal plasticity across development (Fig. 2). Loss-of-function studies have established that proper astrocyte (Ribot et al., 2021) and oligodendrocyte maturation (Xin et al., 2024) are required for limiting neuronal plasticity in cortical circuits beyond a critical developmental window. Though less direct, it is also plausible that microglia can regulate the timing of critical periods via deposition or degradation of ECM components (Nguyen et al., 2020; Gray et al., 2024), regulation of neuronal activity via purinergic signaling (Sipe et al., 2016; Badimon et al., 2020), regulation of astrocyte–synapse interactions (Faust et al., 2024), or direct interactions with excitatory and inhibitory synapses (Gunner et al., 2019; Favuzzi et al., 2021).

Figure 2.

Glial control of critical periods for experience-dependent neuronal plasticity. Schematic of glia–neuron interactions that can influence the timing of critical periods for neuronal plasticity. Astrocyte maturation, and specifically the expression of Cx30, regulates activity of the ECM-degrading enzyme MMP9 via RhoA activation to promote ECM stabilization and interneuron maturation. Astrocytes also enhance dendritic stability by regulating microtubules via neuroligin/neurexin signaling, as well as promote the switch from spike timing-dependent long–term depression to spike timing-dependent long-term potentiation during postnatal development via adenosine signaling. Oligodendrocyte maturation and myelination during adolescence modulate dendritic spine stability, cortical responsiveness to sensory stimuli, and cortical inhibitory synaptic transmission. Microglia regulate PNNs via both deposition and degradation of PNN components, as well as engulf ECM surrounding synapses. Furthermore, there is evidence for astrocyte-to-microglia signaling through IL-33, which influences synaptic ECM engulfment, as well as microglia-to-astrocyte signaling through Wnts during development to influence astrocyte contacts with synapses.

An important future direction will be to determine whether these multicellular processes act in series or in parallel to influence neuronal plasticity and how the maturation of one glial cell type affects the function of another. It is worth noting that many of the highlighted manipulations in different glial cells converge onto the same neurons or neuron-related compartments, including synapses, interneurons, and their associated ECM/PNNs. This convergence implies that different populations of glial cells must act in concert to regulate the same neuronal substrates to favor either stability or plasticity. In this review, we highlighted several recent studies demonstrating glial–glial cross talk in the context of experience-induced synaptic plasticity, including the modulation of OPC-mediated synapse engulfment by microglia in the visual cortex (Auguste et al., 2022) and the regulation of astrocyte–synapse interactions by microglia-derived Wnts in the somatosensory cortex (Faust et al., 2024). However, many other glial–glial interactions may be involved in the process of circuit refinement and experience-dependent plasticity [see Faust et al. (2021) and Raiders et al. (2021) for more comprehensive discussions of mechanisms and signaling implicated in glial-mediated engulfment of synapses]. A more holistic consideration of all cell types in a developing circuit will be required to advance our understanding of cortical maturation and plasticity, as well as illuminate novel, feasible avenues for intervention in the context of neurodevelopmental disorders and regenerative medicine.