Abstract
Classically, neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. Neurexins are cleaved by metalloproteases in an activity-dependent manner, releasing the soluble extracellular domain. Here, we report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side. In both cases, neuroligin-1 expression was required. In immature neurons, calcium influx required N-type calcium channels and stimulated dendritic outgrowth and neuronal survival. In mature glutamatergic neurons the neurexin-1β ectodomain stimulated calcium influx through NMDA-receptors, which increased presynaptic release probability. In contrast, prolonged exposure to the ectodomain led to inhibition of synaptic transmission. This secondary inhibition was activity- and neuroligin-1 dependent and caused by a reduction in the readily-releasable pool of vesicles. A synthetic peptide modeled after the neurexin-1β:neuroligin-1 interaction site reproduced the cellular effects of the neurexin-1β ectodomain. Collectively, our findings demonstrate that the soluble neurexin ectodomain stimulates growth of neurons and exerts acute and chronic effects on trans-synaptic signaling involved in setting synaptic strength.
Highlights
Neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners
To investigate the potential function of the ectodomain of NX-1β, we used a NX-1β ectodomain lacking the splice site 4 (SS4), synthesized as a Fc-chimera. It is well-known that NX-1β lacking SS4 interacts with NL-19,43,44
Our data obtained from immature neurons indicate that NX-1β and NL-1 expressed before s ynaptogenesis[45] can be recruited for neuritogenesis
Summary
Neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. We report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side In both cases, neuroligin-1 expression was required. We find that both the ectodomain and the peptide potently stimulate neuritogenesis in immature neurons and induce an acute (within a few seconds) increase in synaptic strength in mature glutamatergic neurons, which progresses into an activity-dependent homeostatic down-regulation within two hours. These effects are found to be NL-1 and Ca2+-dependent, and indicate that the NX-1β ectodomain is potentially involved in acutely adjusting synaptic strength
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