Astrocyte-Secreted Neurocan Controls Inhibitory Synapse Formation and Function

Abstract

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. To date, several astrocyte-secreted synaptogenic proteins controlling different stages of excitatory synapse development have been identified. However, the identities of astrocytic signals that induce inhibitory synapse formation remain elusive. Here, through a combination of in vitro and in vivo experiments, we identified Neurocan as an astrocyte-secreted inhibitory synaptogenic protein. Neurocan is a chondroitin sulfate proteoglycan that is best known as a protein localized to the perineuronal nets. However, Neurocan is cleaved into two after secretion from astrocytes. We found that the resulting N- and C- terminal fragments have distinct localizations in the extracellular matrix. While the N-terminal fragment remains associated with perineuronal nets, the Neurocan C-terminal fragment localizes to synapses and specifically controls cortical inhibitory synapse formation and function. Neurocan knockout mice lacking the whole protein or only its C-terminal synaptogenic region have reduced inhibitory synapse numbers and function. Through super-resolution microscopy and in vivo proximity labeling by secreted TurboID, we discovered that the synaptogenic domain of Neurocan localizes to somatostatin-positive inhibitory synapses and strongly regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific inhibitory synapse development in the mammalian brain.

Abnormal morphology and synaptogenic signaling in astrocytes following prenatal opioid exposure

“…Opioid exposure increases proinflammatory cytokine secretion by astrocytes [50], which may in turn affect downstream production and/or release of synapse-mediating factors such as hevin and SPARC. In addition to regulating excitatory glutamatergic synaptogenesis, astrocytes have also been shown to promote the formation of inhibitory GABAergic synapses [51, 52]; these possibilities are currently being investigated.…”

Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons

“…Consistent with our findings, a recent investigation proposed that astrocyte-secreted Ncan has a critical function in preserving the integrity of inhibitory synapses. The Eroglu lab showed in a preprint that Ncan deletion reduces the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in cortical neurons of Ncan KO mice (Irala et al, 2023).…”

Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis

“…Astrocytes also play an important neurodevelopmental role in synapse formation and maintenance, hypothesised to underlie the pathophysiology of psychosis 51 and other psychiatric disorders 52 . Interestingly, astrocytes are also important for the formation of perineuronal nets, as well as contributing to maintaining excitatory/inhibitory balance 53 , both proposed to be involved in the pathophysiology of psychosis 54 . Our correlations were robust for most sensitivity analyses, though did not survive FDR correction in our medication status sensitivity analysis in CHR-P or CHR-T.…”