Compartment-Specific Neurexin Nanodomains Orchestrate Tripartite Synapse Assembly

Abstract

At tripartite synapses, astrocytes surround synaptic contacts, but how astrocytes contribute to the assembly and function of synapses remains unclear. Here we show that neurexin-1α, a presynaptic adhesion molecule that controls synapse properties, is also abundantly expressed by astrocytes. Strikingly, astrocytic neurexin-1α, but not neuronal neurexin-1α, is highly modified by heparan sulfate. Moreover, astrocytic neurexin-1α is uniquely alternatively spliced and invariably contains an insert in splice-site #4, thereby restricting the range of ligands to which it binds. Deletion of neurexin-1 from astrocytes or neurons does not alter synapse numbers or synapse ultrastructure, but differentially impairs synapse function. At hippocampal Schaffer-collateral synapses, neuronal neurexin-1 is essential for normal NMDA-receptor-mediated synaptic responses, whereas astrocytic neurexin-1 is required for normal AMPA-receptor-mediated synaptic responses and for long-term potentiation of these responses. Thus, astrocytes directly shape synapse properties via a neurexin-1-dependent mechanism that involves a specific molecular program distinct from that of neuronal neurexin-1.

The Perils of Navigating Activity-Dependent Alternative Splicing of Neurexins

“…Astrocytes express high levels of Nrxn1 similar to neurons, but astrocytic Nrxn1 is primarily present as Nrxn1-SS4+ whereas neuronal Nrxn1 is a mixture of Nrxn1-SS4+ and Nrxn1-SS4– (Trotter et al, 2020 ). Examination of the Alternative Splicing and Gene Expression Summaries of Public RNAseq Data [ASCOT; http://ascot.cs.jhu.edu/ (Ling et al, 2020 )] showed that Nrxn1-SS4 is differentially spliced between neurons and astroglial cells.…”

Instructive roles of astrocytes in hippocampal synaptic plasticity: neuronal activity‐dependent regulatory mechanisms

“…The neurexin/ neuroligin and ephrin/Eph receptor-mediated contacts between astrocytic processes and synaptic terminals have been reported to regulate astrocyte-mediated synaptic plasticity [79][80][81][82][83][84]. Of note, the deletion of Nrxn1 (neurexin-1) in astrocytes but not in neurons suppresses AMPAR-mediated excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons of acute hippocampal slices, suggesting that astrocytic Nrxn1 interacts with neuronal neuroligins to regulate excitatory synaptic transmission through the modulation of AMPAR response [84]. Meanwhile, ephrins expressed by astrocytes regulate dendritic spine formation and elimination as well as synaptic plasticity through the activation of neuronal Eph receptors (Fig.…”

Modulating glial genes involved in synaptic function mitigates pathogenesis and behavioral deficits in aDrosophilamodel of Huntington’s Disease

“…The hyperfunction of a given brain region puts considerable strain on the circuit, and it seems that over the course of a lifetime, the brain keeps trying to compensate for the abnormalities that arise at different stages of HD. The recent observation that deletion of astrocytic neurexin-1α attenuates synaptic transmission but not synapse number supports this hypothesis (Trotter et al, 2020).…”