Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin

Abstract

SUMMARY 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-1α and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1α 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.

Cell Biology of Astrocyte-Synapse Interactions

“…The synapses induced by these signals contain all of the structural elements of a synapse (such as presynaptic vesicles, active release sites and postsynaptic density) and are presynaptically active because they release and reuptake synaptic vesicles. However, they are postsynaptically silent synapses, because they contain only NMDA glutamate receptors, but lack AMPA glutamate receptors (Christopherson et al, 2005; Singh et al, 2016). Interestingly, astrocytes also produce an antagonist of the prosynaptogenic Hevin, called SPARC (Kucukdereli et al, 2011).…”

“…Hippocampal slices prepared from TNFα KO mice show normal LTP and long term depression (LTD), but no increase in synaptic strength in response to prolonged activity deprivation. Mice lacking Hevin (Hevin KO) do not show a form of in vivo plasticity called ocular dominance plasticity, where synapses in the visual cortex remodel in response to changed visual experience (Singh et al, 2016). Rescue of Hevin expression specifically in developing visual cortex astrocytes of the Hevin KOs resulted in restoration of ocular dominance plasticity, showing that astrocytic expression of Hevin is sufficient to control this form of plasticity (Singh et al, 2016).…”

“…Mice lacking Hevin (Hevin KO) do not show a form of in vivo plasticity called ocular dominance plasticity, where synapses in the visual cortex remodel in response to changed visual experience (Singh et al, 2016). Rescue of Hevin expression specifically in developing visual cortex astrocytes of the Hevin KOs resulted in restoration of ocular dominance plasticity, showing that astrocytic expression of Hevin is sufficient to control this form of plasticity (Singh et al, 2016). Ocular dominance plasticity occurs through a combination of LTD, LTP and homeostatic scaling (Espinosa and Stryker, 2012), so it will be important to determine which of these plasticity mechanisms is defective in Hevin null mice.…”

“…On the other hand, Hevin regulates formation of thalamocortical glutamatergic synapses by bridging presynaptic neurexin-1alpha (NRX1α) with postsynaptic neuroligin-1B (NL1B) (Singh et al, 2016), two neuronal cell adhesion molecules that do not interact with each other. A region within Hevin interacts concurrently with the extracellular domains of NRX1α and NL1B.…”

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

“…Importantly, Drosophila Ube3a (dUbe3a) is highly homologous to human Ube3a (hUbe3a) (34). Nrx-1 and Nlg4 are involved in synapse formation, maturation, and plasticity (35)(36)(37). Tsc1 is a negative regulator in the mTORC1 pathway (38-42) which regulates cell growth and proliferation in flies (43).…”