Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism. [Display omitted] •Astrocyte-secreted hevin is a pre- and postsynaptic organizer•Hevin induces thalamocortical synapse formation by bridging NRX1α and NL1•Hevin is required for recruitment of NL1 and NMDAR to excitatory synapses in vivo•Astrocyte-secreted hevin is necessary for ocular dominance plasticity Astrocytes promote synapse formation and plasticity by secreting a protein that bridges non-interacting isoforms of neurexin and neuroligin, suggesting an additional layer of complexity to the isoform code that dictates synaptic adhesion.