Elsevier

Neurochemistry International

Volume 45, Issue 4, September 2004, Pages 491-501
Neurochemistry International

Neuronal, glial and synaptic remodeling in the adult hypothalamus: functional consequences and role of cell surface and extracellular matrix adhesion molecules

https://doi.org/10.1016/j.neuint.2003.11.003Get rights and content

Abstract

The adult hypothalamo-neurohypophysial system (HNS) undergoes activity-dependent morphological plasticity which modifies astrocytic coverage of its oxytocinergic neurons and their synaptic inputs. Thus, during physiological conditions that enhance central and peripheral release of oxytocin (OT), adjacent somata and dendrites of OT neurons become extensively juxtaposed, without intervening astrocytic processes and receive an increased number of synapses. The morphological changes occur within a few hours and are reversible with termination of stimulation. The reduced astrocytic coverage has direct functional consequences since it modifies extracellular ionic homeostasis, synaptic transmission, and the size and geometry of the extracellular space. It also contributes indirectly to neuronal function by permitting formation of synapses on neuronal surfaces freed of astrocytic processes. Overall, such remodeling is expected to potentiate activated neuronal firing, especially in clusters of tightly packed neurons, an anatomical arrangement characterizing OT neurons. This plasticity connotes dynamic cell interactions that must bring into play cell surface and extracellular matrix adhesive proteins like those intervening in developing neuronal systems undergoing neuronal–glial and synaptogenic transformations. It is worth noting, therefore, that adult HNS neurons and glia continue to express such molecules, including polysialic acid (PSA)-enriched neural cell adhesion molecule (PSA-NCAM) and the glycoprotein, tenascin-C. PSA is a large, complex sugar on the extracellular domain of NCAM considered a negative regulator of adhesion; it occurs in large amounts on the surfaces of HNS neurons and astrocytes. Tenascin-C, on the other hand, possesses adhesive and repulsive properties; it is secreted by HNS astrocytes and occurs in extracellular spaces and on cell surfaces after interaction with appropriate ligands. These molecules have been considered permissive factors for morphological plasticity. However, because of their localization and inherent properties, they may also serve to modulate the extracellular environment and in consequence, synaptic and volume transmission in a system in which the extracellular compartment is constantly being modified.

Introduction

Cells of the adult CNS, as well as the synapses that control their activities, are not static but can undergo dynamic transformations that alter their morphologies and interrelationships. This occurs even under normal physiological conditions and highlights the nervous system’s remarkable capacity to undergo restructuring to meet particular functional requirements. A change in the morphology of particular neurons and their synaptic inputs may be of direct consequence to their respective functions. In addition, remodeling of neurons, as well as of neighboring glia, may have further consequences on neuronal and glial behavior since it will modify the immediate extracellular microenvironment, with consequences on synaptic and volume transmission.

The oxytocinergic system of the hypothalamus is a familiar model of this form of neuronal and glial plasticity. Released from axon terminals in the neurohypophysis, oxytocin (OT) acts as a neurohormone and intervenes in vital functions like parturition, lactation and osmotic regulation; released centrally, it facilitates the activity of its own system and participates in several neurovegetative and limbic functions (reviewed in Richard et al., 1991). Under stimulation, OT neurons display distinct patterns of electrical and secretory activities (see Poulain and Wakerley, 1982). At the same time, their overall morphology is modified since they progressively hypertrophy, their dendrites shorten and display few branches while their axons enlarge and ramify. These changes in neuronal morphology occur together with modifications in the morphology of adjacent glia (astrocytes in the hypothalamus and astrocyte-like pituicytes in the neurohypophysis) and synaptic inputs controlling the activity of the neurons. Several recent reviews describe this morphological neuronal and glial plasticity in detail (Theodosis and MacVicar, 1996, Miyata and Hatton, 2002, Theodosis, 2002) and we will here present only its most salient features as it occurs in the hypothalamic magnocellular nuclei in which OT neurons are localized.

The supraoptic nucleus (SON) and magnocellular portions of the paraventricular nucleus (PVN) are well-defined, relatively homogeneous nuclei composed essentially of the somata and dendrites of neurons secreting OT or vasopressin (VP), astrocytes and vascular elements. It is noteworthy that there are at least three major types of astrocytes in the SON. There are stellate (protoplasmic) astrocytes, similar to those found elsewhere in the adult CNS, interspersed anywhere in the SON. The most numerous, however, are radial glia-like astrocytes whose cell bodies are lined up along the base of the brain (the ventral glial lamina or VGL) which send thick processes in the dorso-ventral direction through the nucleus (Bonfanti et al., 1993, Bobak and Salm, 1996, Israel et al., 2003b). In ongoing experiments using specific intracellular labeling of SON astrocytes, we have noted that both the stellate and the radial type emit fine processes which separate neuronal elements (A. Trailin, K. Bauer, D.T. Theodosis, unpublished observations). In addition, we recently detected yet another population of astrocytes, which are small and round and have few processes and are present in the VGL close to the subarachnoid space (Israel et al., 2003b). Not only do SON astrocytes vary in relation to mophology and location, but, based on differential expression of ionic channels, neurotransmitter receptors and transporters, they present different electrophysiological characteristics as well (Israel et al., 2003b), a heterogeneity that must be taken into account when considering their contribution to extracellular homeostasis.

In the magnocellular nuclei, OT neurons often occur in tightly packed clusters or pairs intermingled with VP neurons. Electron microscopy shows clearly, however, that in spite of their tight packing, they remain separated by neuropil elements and especially by the fine, lamella-like processes of astrocytes (Fig. 1A). Such an astrocytic coverage of neuronal profiles characterizes most adult neuronal tissues, as it does the OT system under basal conditions of neurosecretion. In contrast, when it is stimulated (during parturition, lactation, osmotic stimulation, stress), glial coverage of OT somata and dendrites significantly diminishes and their surfaces are left directly juxtaposed (Fig. 1B). Upon arrest of stimulation, astrocytic processes reappear to separate neuronal profiles. These dynamic astroglial and neuronal changes can be evaluated by comparing the incidence and extent of direct neuronal juxtapositions in magnocellular nuclei of rats under various conditions of OT secretion. Moreover, when ultrastructural analysis is performed on immunoidentified profiles, one sees without ambiguity that the neuronal–glial changes are specific to the OT system, regardless of the physiological or experimental condition, or the location of the neurons (Chapman et al., 1986, Theodosis et al., 1986a, Theodosis et al., 1986b, Theodosis and Poulain, 1987, Theodosis and Poulain, 1989, Langle et al., 2003). It should be noted that the surfaces of VP somata and dendrites also display juxtapositions but their incidence and extent are low. Moreover, they do not vary with changing conditions of neurosecretion (Chapman et al., 1986, Theodosis et al., 1986a, Theodosis and Poulain, 1989, Langle et al., 2003).

The activity-dependent reduction in glial coverage of neuronal elements in the hypothalamo-neurohypophysial system (HNS) occurs rapidly. In vivo studies showed an increased incidence of neuronal juxtapositions within a few hours after the onset of parturition (Montagnese et al., 1987) and osmotic stimulation (Tweedle and Hatton, 1977). More recent in vitro analyses performed on acute hypothalamic slices containing the SON revealed an increased incidence even within 1 h after stimulation (Langle et al., 2003). On the other hand, the rapidity with which the magnocellular nuclei revert to their unstimulated morphologies depends on the duration of stimulation (Chapman et al., 1986, Montagnese et al., 1987, Langle et al., 2003).

Whether juxtaposed neuronal surfaces are a consequence simply of glial retraction is still an unanswered question. What is highly unlikely is that astrocytic processes are passively squeezed away by hypertrophied neuronal profiles. This mechanism, for instance, does not explain the significant reduction in astrocytic coverage of dendrites which often occur in directly juxtaposed bundles throughout the remodeled nuclei. In addition, while VP neurons greatly hypertrophy under a stimulus like chronic dehydration, their surfaces do not display an increased incidence of juxtapositions (Chapman et al., 1986). A more likely explanation is that neuronal juxtapositions result both from active retraction and elongation of glial processes over neuronal surfaces whose morphology is constantly changing (see also Theodosis, 2002). It is also highly probable that the modified expression of several cytoskeletal proteins in HNS neurons and glia (Nothias et al., 1996, Hawrylak et al., 1999, Miyata et al., 1999) is linked to this remodeling.

In the magnocellular nuclei, the neuronal–glial conformational changes are invariably accompanied by a changing number of synaptic contacts, anatomical rearrangements that would affect further neuronal connectivity and in consequence, neuronal function. This is particularly true for boutons making synaptic contacts onto more than one post-synaptic element simultaneously (“multiple synaptic boutons”) (Fig. 1B). Visible in the magnocellular nuclei under all conditions, their incidence significantly increases during conditions of enhanced or sustained OT release. Here again, such an increase affects only those boutons synapsing onto OT profiles (reviewed in Theodosis and Poulain, 1987). It is noteworthy that they often bridge OT somata and dendrites whose surfaces are in extensive juxtaposition (Fig. 1B). In more recent analyses, we established that synaptic proliferation in this area of the hypothalamus is more extensive than thought originally since it concerns terminals making single synaptic contact as well (Gies and Theodosis, 1994, El Majdoubi et al., 1996, Michaloudi et al., 1997, El Majdoubi et al., 1997). Like the formation of neuronal surface juxtapositions, the creation of new synapses occurs quite rapidly. In vivo, an increased incidence of synaptic contacts was noted within 24 h after the onset of stimulation (see Theodosis, 2002) while in vitro, a significant increase is detectable within 4 h (Langle et al., 2003). The rate at which the incidence of synaptic contacts returns to unstimulated levels depends on the duration of stimulation (Theodosis, 2002).

The perception of the role of glia in nervous system function has changed dramatically over the past 15 years, from that of simple supporting ‘glue’ with mainly trophic functions, to that of cells with potential for dynamic interactions with neurons, thereby actively participating in neural function. This is due essentially to the development of new techniques like patch clamp recordings and optical imaging that allowed to show that glia express a variety of ion channels, neurotransmitter receptors and transporters that enable them to respond to neuronal activity (for a review see Verkhratsky et al., 1998). The current general view is that astrocytes in the CNS and Schwann cells in the PNS surround neuronal profiles and help maintain the extracellular environment by providing physical integrity and regulating extracellular ionic and neurotransmitter homeostasis. As demonstrated by several studies, astrocytic coverage of hypothalamic magnocellular neurons is indeed of such import to their particular activities.

A primary function of astrocytes is to buffer K+ ions released in the extracellular space during neuronal electrical activity. It was not too surprising to discover, therefore, that the reduced astrocytic coverage of OT neurons during lactation results in a delayed clearance of K+, at least in the SON (Coles and Poulain, 1991). The accumulation of extracellular K+ was highly localized and of short duration. Nevertheless, local accumulation of extracellular K+ could increase the excitability of adjacent neurons, a phenomenon that could be of particular relevance in clusters of directly juxtaposed OT neurons to facilitate their characteristic synchronization of firing at lactation.

Another major function of astrocytes is clearance of glutamate from perisynaptic areas via specific transporters, such as GLT-1 (reviewed in Bergles et al., 1999). Modification in the degree of astrocytic coverage of neurons, therefore, may have important repercussions on the concentration and diffusion of glutamate in the extracellular space. We recently showed that glutamate uptake was indeed deficient in the SON of lactating rats, a deficiency which increases the level of activation of group III pre-synaptic metabotropic glutamate receptors (mGluRs III) on glutamatergic terminals (Fig. 2) (Oliet et al., 2001). Since activation of mGluRs III inhibits transmitter release (Schrader and Tasker, 1997b, Oliet et al., 2001, Piet et al., 2003), tonic negative feedback of glutamate on its own release is enhanced in the SON of lactating rats (Oliet et al., 2001). A similar phenomenon has been reported recently in the SON of chronically dehydrated rats (Boudaba et al., 2003) in which, as noted earlier, neuroglial plasticity of the OT system occurs as well (Chapman et al., 1986). Thus, a major consequence of diminished astrocytic coverage of magnocellular neurons is decreased efficacy of the excitatory neurotransmission driving their activity. Inhibition of glutamate release at a time when there is a high demand for OT secretion may appear paradoxical, especially in a system where the major excitatory drive to OT neurons derives from glutamate synapses (El Majdoubi et al., 1997, Jourdain et al., 1998, Israel et al., 2003a). However, this form of presynaptic inhibition should be considered in relation to the level of ongoing activity at these synapses where it could constitute a high pass filter of excitatory neurotransmission by which high frequency activity would be favored over low to moderate activities (see also Oliet, 2002).

Presynaptic inhibition of glutamate synapses by glutamate appears to be a highly localized phenomenon in the SON since mGluRs III on distant inhibitory GABAergic terminals are not tonically activated by ambient glutamate in unstimulated or stimulated conditions (Schrader and Tasker, 1997b, Piet et al., 2003). Nevertheless, activity-dependent modulation of GABA transmission via mGluRs IIIs could take place during strong and sustained stimulation of glutamatergic afferent inputs to magnocellular neurons, as described in other central systems (Min et al., 1999, Sakake et al., 2000, Semyanov and Kullmann, 2000).

Morphological neuronal–glial changes may have additional direct consequences on the function of magnocellular neurons. First, it is not unlikely that the glutamate uptake deficiency associated with astrocytic process withdrawal may affect glutamate receptors other than mGluRIIIs. Likely candidates are NMDA and mGluRI receptors, located on magnocellular neurons (Hu and Bourque, 1991, Schrader and Tasker, 1997a) which display high affinity for glutamate. Secondly, astrocytes participate in the clearance of other neurotransmitters, like GABA (reviewed in Schousboe, 2003). Since GABAergic synapses represent over 40% of all synapses in the SON (for a review see El Majdoubi et al., 2000), any modulation of GABAergic transmission would have strong repercussions on the electrical activity of magnocellular neurons. Thirdly, in addition to participation in the maintenance of the ionic and neurotransmitter extracellular homeostasis, the processes of astrocytes, by their location and enveloping of neuronal elements, represent a physical barrier to diffusion of molecules in the extracellular space (ECS) (Sykova, 2001).

The ECS constitutes a communication channel for substances implicated in extrasynaptic or volume transmission. Diffusion within the tissue is dictated by several parameters including the presence of astrocytic processes, charged molecules, degrading enzymes, extracellular matrix components and cellular uptake. Studies performed in the developing, aging or lesioned central nervous system have indicated that changes in the astrocytic environment of neurons can markedly modify the size and geometry of the ECS (Sykova, 2001). It is highly likely then, that the lack of astrocytic processes around magnocellular neurons associated with stimuli like lactation would affect ECS diffusion properties. We tested this possibility recently using the real time tetramethymammonium iontophoretic method that permits measurement of tortuosity, an index of the restriction imposed on diffusion by the tissue, volume fraction, or the volume of tissue available for diffusion, and non-specific uptake (Nicholson and Sykova, 1998). Analysis of these parameters revealed that tortuosity and volume fraction were significantly reduced in the SON of lactating rats (Vargova et al., 2003). In addition, diffusion that was not equivalent in all directions (anisotropic) in the SON of virgin rats became isotropic (equivalent in all directions) in lactating animals. Taken together, these data strongly suggest that under conditions of diminished astrocytic coverage of neurons diffusion is facilitated and occurs in a smaller volume (Vargova et al., 2002). This form of facilitation may affect diffusion of neuroactive substances other than neurotransmitters, like OT and VP, which are also released locally in the magnocellular nuclei (see Richard et al., 1991) and which could facilitate cell–cell communication and extrasynaptic transmission. It is likely, therefore, that the morphological remodeling of the SON will enhance dramatically the concentration and the range of action of any neuroactive substance released in the tissue.

An important indirect functional consequence of a modified glial coverage is to permit the synaptic rearrangements occurring concurrently. As clearly shown by our analyses of immunolabeled ultrathin sections, synaptic remodeling in the magnocellular nuclei modifies excitatory (glutamate, noradrenaline) as well inhibitory (GABA) afferent inputs to OT neurons (see El Majdoubi et al., 2000). Physiological consequences of such synapse proliferation are illustrated by increases in spontaneous synaptic currents (Brussaard et al., 1999, Stern et al., 2000). It is possible that these increases simply provide a compensatory mechanism for the hypertrophy of OT cells during stimulation (Modney and Hatton, 1989, Gies and Theodosis, 1994, El Majdoubi et al., 1996), providing an afferent regulation equivalent to that under unstimulated conditions. Nevertheless, an increase in the incidence of synaptic contacts is detected even before the post-synaptic elements significantly hypertrophy (El Majdoubi et al., 1997, Langle et al., 2003), and this raises the additional possibility that an increased number of synapses intervene more directly to regulate the particular electrical activity displayed by OT neurons during stimulation (Poulain and Wakerley, 1982).

As noted earlier, neuronal, glial and synaptic conformational changes in the HNS are reversible with cessation of stimulation, occurring upon each new stimulation (Theodosis and Poulain, 1993, Theodosis and MacVicar, 1996, Hatton, 1997). Such morphological changes represent, therefore, very dynamic cell interactions which must modify adhesive interactions mediated by cell surface glycoproteins like those of the immunoglobulin (Ig) superfamily (reviewed in Edelman and Crossin, 1991) and the cadherins (Takeichi, 1988), and extracellular matrix (ECM) molecules like laminins, proeoglycans and tenascins (Faissner et al., 1994). The adult HNS expresses many of these molecules (see Theodosis, 2002). We will here focus our attention on the expression of the neural cell adhesion molecule (NCAM) isoform highly enriched in polysialic acid (PSA), and the ECM glycoprotein, tenascin-C which, until now, have been considered important only as permissive factors for the morphological plasticity of the HNS. However, because of their localization and inherent properties, they can also be viewed as crucial actors in the modulation of the extracellular compartment, and in consequence, in the fine tuning of HNS function.

NCAM is probably the most extensively studied cell adhesion molecule and is thought to intervene in most cell interactions via modulation of cell adhesivity and intracellular signaling (for a review see Edelman and Crossin, 1991). It occurs in structurally distinct isoforms whose complex Ig and fibronectin domains cover cell surfaces. In principle, then, regulation of NCAM-mediated interactions can be achieved by transcriptional control of the type and amount of NCAM expressed on the cell surface. Further regulatory possibilities are provided by the posttranslational addition of the unique carbohydrate polymer, α-2–8-linked polysialic acid (PSA), on its extracellular domain (reviewed in Rougon, 1993). The resulting high Mr isoform (about 220 kD), known as PSA-NCAM, contains more than 30% PSA attached to its 5th Ig-like domain. NCAM is highly sialylated in embryonic tissues, whereas most adult tissues contain NCAM with little PSA. The cellular mechanisms affected by PSA have been elucidated primarily through the study of developing systems where PSA promotes dynamic phenomena like cell migration, axon guidance, and axon selection of synaptic targets (see Rutishauser and Landmesser, 1996).

PSA-NCAM continues to be expressed in areas of the adult CNS endowed with the capacity for morphological and/or physiological plasticity (Bonfanti et al., 1992, Seki and Arai, 1993), of which the HNS is particularly striking (Theodosis et al., 1991, Bonfanti et al., 1992, Kiss et al., 1993, Nothias et al., 1997). It is especially conspicuous in HNS astrocytes (Fig. 3) but occurs in HNS neurons as well where its surface expression appears polarized to dendritic and axonal surfaces (Theodosis et al., 1999, Pierre et al., 2001). Levels of PSA-NCAM do not vary greatly in relation to different conditions of HNS neurosecretion (Theodosis et al., 1991, Bonfanti et al., 1992, Theodosis et al., 1999) since the glycoprotein reaches cell surfaces via the activitiy-independent constitutive pathway (Pierre et al., 2001). Nevertheless, this does not mean that its expression is of no consequence to activity-dependent morphological plasticity. In recent analyses, we found that specific enzymatic removal of PSA from NCAM in one SON in situ inhibited the neuronal, glial and synaptic changes expected to occur in response to lactation or chronic dehydration; the controlateral SON remained unaffected by the enzymatic treatment and underwent remodeling (Theodosis et al., 1999). The cell mechanisms by which PSA intervenes to permit the morphological changes remain unknown. Our observations are in agreement with a mechanism whereby large quantities of PSA on extracellular surfaces would attenuate adhesion via physical impedance or charge repulsion, thus allowing dynamic structural modifications (Rutishauser and Landmesser, 1996). Cells could then detach from their neighbors or from the extracellular matrix and be able to undergo changes in conformation related to remodeling.

In view of the above, PSA-NCAM can be considered a necessary permissive factor for morphological glial and neuronal plasticity, allowing HNS cells and synapses to undergo remodeling whenever the proper stimulus intervenes. In the hypothalamic magnocellular nuclei, one such stimulus is OT itself since it can induce morphological changes similar to those observed under physiological stimulation, rapidly and reliably, via an activity-dependent, receptor-, calcium-mediated mechanism (Theodosis et al., 1986b, Langle et al., 2003). In other neuronal systems capable of morphological plasticity and expressing PSA-NCAM (Bonfanti et al., 1992, Hoyk et al., 2001, Muller et al., 1996, Shen et al., 1997), other inductive factors must intervene.

Both adhesive and repulsive or anti-adhesive molecules are responsible for neuron-glia conformational interactions. Tenascins, a family of large ECM glycoproteins, can intervene in these interactions since they exert both inhibitory and stimulatory effects. In particular, tenascin-C is considered an anti-adhesive protein and thus an excellent candidate to permit retraction of glial processes. Like NCAM, tenascin-C is a glycoprotein expressed in specific patterns with respect to location and timing during development and down regulated after maturation; its expression persists in restricted areas of the mature CNS exhibiting plasticity, including the HNS, as well as being reexpressed after lesion (reviewed in Joester and Faissner, 2003). Tenascin-C occurs in a large number of isoform variants generated by combinational variation of alternatively-spliced fibronectin type III repeats, indicating that it may specify the neural microenvironment, a suggestion supported by recent analysis of tenascin-C knockout mice (Joester and Faissner, 2003).Tenascin-C is secreted primarily by immature and reactive astrocytes and by subsets of radial glia (Joester and Faissner, 2003, Dityatev and Schachner, 2003). In the adult, its expression persists in a very discrete manner, as exemplified by the HNS (Fig. 4) (Theodosis et al., 1994, Singleton and Salm, 1996, Theodosis et al., 1997). The molecule reacts with various ligands including the integrins, F3/contactin and phosphocan, a glia-derived chondroitin sulphate proteoglycan which forms a complex in the extracellular space whose size and molecular complexity would certainly affect the latter. Further complexity can result after interaction with ECM components like heparin and/or collagens, interactions which would not only intervene in intracellular signaling mechanisms but, additionally, in interactions that could physically alter the ECM and its diffusion modalities (see also Dityatev and Schachner, 2003, Joester and Faissner, 2003) Nevertheless, the functional significance of this molecule continues to be a puzzle, especially since mice genetically deprived of tenascin-C do not show an overtly abnormal phenotype (Joester and Faissner, 2003).

Tenascin-C is thought to actively intervene in neuronal–glial conformational changes during development and after lesion (Joester and Faissner, 2003), but its actual contribution to the morphological plasticity of the HNS remains to be determined. Like PSA-NCAM, its expression does not greatly vary with HNS stimulation (Theodosis et al., 1997). It can be considered, therefore, as another permissive molecular factor intervening to inhibit or enhance neuronal–glial attachments after interaction with ligands like F3/contactin or phosphocan, proteins highly expressed in the adult HNS as well (Pierre et al., 1998, Theodosis et al., 2000, Miyata et al., 2001).

In addition to their roles as permissive molecular factors for morphological plasticity, PSA-NCAM and tenascin-C, may serve to regulate the extracellular environment. There are several possibilities. The first, and perhaps, the most obvious, is that their molecular interactions, by permitting or inhibiting neuronal glial remodeling, will affect the presence of astrocytic processes in extracellular spaces. As discussed earlier, the mere physical presence of astrocytic processes has serious repercussions on the diffusion parameters of the extracellular compartment, parameters which then intervene in the control of neuronal function. Second, both PSA on NCAM and tenascin-C, by their very location and composition, may affect the extracellular milieu directly. For example, their presence may hinder access to receptors and transporters, thereby modulating the potential action of neuroactive substances. Moreover, they may interact heterophilically with other ECM molecules, including growth factors, laminins, integrins, and other members of the Ig superfamily and this would have important consequences on neuronal activity (for review and further discussion see Kiss and Muller, 2001, Dityatev and Schachner, 2003). In this context, it is noteworthy that these molecules are excluded from the extracellular space between directly juxtaposed neuronal surfaces in the remodeled HNS (Fig. 3), thus highlighting molecular transformation of the ECM and in consequence, of its diffusion parameters under such conditions.

Section snippets

Conclusions

That astrocytes contribute actively in the regulation of neuronal function has been amply and convincingly demonstrated. A major means is by preventing the accumulation of neuroactive substances in the ECM, a process which depends on an intact astrocytic coverage of neuronal elements and, especially synapses. In addition, astrocytes express on their surfaces and secrete other substances into the ECM, which by their size and complexity can alter its molecular composition, thereby modifying its

Acknowledgements

Part of this work was supported by grants from the Conseil Régional d’Aquitaine and the Fondation pour la Recherche Médicale. S.H.R.O. is the recipient of an Action Concertée Initiative Jeunes Chercheurs from the Ministère de la Recherche, R.P. was supported by a scholarship from the Ministère de l’Education Nationale, de la Recherche et de la Technologie.

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