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Wiring synaptic circuits with astroglial connexins: mechanisms, dynamics and impact for critical period plasticity

Periodic Reporting for period 3 - AstroWireSyn (Wiring synaptic circuits with astroglial connexins: mechanisms, dynamics and impact for critical period plasticity)

Reporting period: 2019-10-01 to 2021-03-31

Brain information processing is commonly thought to be a neuronal performance. However recent data point to a key role of astrocytes in brain development, activity and pathology. Indeed astrocytes are now viewed as crucial elements of the brain circuitry that control synapse formation, maturation, activity and elimination. How do astrocytes exert such control is matter of intense research, as they are now known to participate in critical developmental periods as well as in psychiatric disorders involving synapse alterations. Thus unraveling how astrocytes control synaptic circuit formation and maturation is crucial, not only for our understanding of brain development, but also for identifying novel therapeutic targets.
We recently found that connexin 30 (Cx30), an astroglial gap junction subunit expressed postnatally, tunes synaptic activity via an unprecedented non-channel function setting the proximity of glial processes to synaptic clefts, essential for synaptic glutamate clearance efficacy. Our work not only reveals Cx30 as a key determinant of glial synapse coverage, but also extends the classical model of neuroglial interactions in which astrocytes are generally considered as extrasynaptic elements indirectly regulating neurotransmission. Yet the molecular mechanisms involved in such control, its dynamic regulation by activity and impact in a native developmental context are unknown. We will now address these important questions, focusing on the involvement of this novel astroglial function in wiring developing synaptic circuits.
Thus using a multidisciplinary approach we will investigate:
1) the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function
2) the activity-dependent dynamics of Cx30 function at synapses
3) a role for Cx30 in wiring synaptic circuits during critical developmental periods
This ambitious project will provide essential knowledge on the molecular mechanisms underlying astroglial control of synaptic circuits.
During these first 30 months, we have addressed the molecular and cellular mechanisms underlying Cx30 regulation of synaptic function.
We have shown in vitro and in situ that Cx30 regulates astrocyte polarization during postnatal brain development (Ghezali et al., 2018, Development). We indeed found that Cx30, independently of its gap-junction mediated biochemical coupling function, controls the orientation of astroglial protrusion during polarized migration via modulation of the laminin/1 integrin/cdc42 polarity pathway. Connexin 30 indeed reduces laminin levels, inhibits the redistribution of the β1-integrin extracellular matrix receptors, and inhibits the recruitment and activation of the small Rho GTPase Cdc42 at the leading edge of migrating astrocytes. In vivo Cx30, the expression of which is developmentally regulated, also contributes to the establishment of hippocampal astrocyte polarity during postnatal maturation. This study thus reveals that connexin 30 controls astroglial polarity during development.
We have also started to address the activity-dependent dynamics of Cx30 function at synapses. In particular, we have addressed the activity-dependent regulation of Cx30 expression localization as well as functions. We showed that bursting activity increases hippocampal Cx30 protein levels via a calcium-dependent and post-translational mechanism regulating lysosomal degradation. Neuronal activity also increased Cx30 protein levels at membranes and perisynaptic processes, as revealed by super-resolution imaging. Remarkably, the activity-dependent control of Cx30 protein levels and localization that we found translated at the functional level in the activation of Cx30 hemichannels, and in Cx30-mediated remodeling of astrocyte morphology independently of gap junction biochemical coupling. Altogether these data show activity-dependent dynamics of Cx30 expression, perisynaptic localization and functions.
Finally, we have also started addressing the impact of astroglial Cx30 on critical period of plasticity, and found that Cx30 controls ocular dominance plasticity in the visual cortex.
In all, these data provide fundamental knowledge on the molecular and cellular mechanisms mediating astroglial regulation of synaptic networks.
This ambitious project should provide essential knowledge on the molecular mechanisms underlying astroglial control of functional synaptic circuits with repercussions in health and disease. In particular, it will determine how an original molecular mechanism controlling invasion or retraction of astroglial processes from synaptic clefts is dynamically involved in synaptic wiring underlying learning and memory, as well as cortical plasticity and oscillations associated with sensory inputs during critical periods. Neural circuits shaped by early experience determine performance. Although one can learn throughout life, learning capacity is matchless in young subjects due to enhanced plasticity. Remarkably, brain lesions in adults can partly revert local circuits to a transiently immature plastic state favoring recovery. Getting insights into the molecular basis of developmental critical period should thus help establishing new strategies to reinduce enhanced plasticity in adults and favors rehabilitation after brain damage. Finally, understanding how astrocytes control the development of functional synaptic circuits will also generate a novel framework for identifying mechanisms underlying neurological or psychiatric disorders resulting from synaptic circuit alterations, thus setting ground for future clinical investigations.