The soluble neurexin-1β ectodomain causes calcium influx and augments dendritic outgrowth and synaptic transmission

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.

Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?

“…Schizophrenia-associated genes encoding molecules involved in neurite and synaptic development may also exert an effect on synaptic activity and remodeling in the adult human brain. For example, NRXN1 is reported to increase Ca 2+ influx through the NMDA receptor ( 86 ) and its splicing to affect the stability of hippocampal fear memories ( 87 ), while TRIO has been shown to support glutamatergic transmission and long-term potentiation in rodent hippocampal slice cultures ( 88 ). We believe that a systematic assessment of the role of well-supported schizophrenia susceptibility genes in both synaptic development and adult synaptic function is now warranted, with genes implicated through exome sequencing and fine-mapping of nonsynonymous coding variants prioritized and with due attention to the specific RNA transcripts affected by genetic risk variation.…”

Development of Liposomes That Target Axon Terminals Encapsulating Berberine in Cultured Primary Neurons

“…Neurexin involves cell adhesion molecules that are abundantly expressed in axon terminals with three extracellular epidermal growth factor-like domains (EGF) and six laminin-neurexin sex-hormone-binding globulin domains (LNS). For the peptides targeting axon terminals, we used a Carbonic Anhydrase-related Protein (CAP), a secreted glycoprotein identified by the proteomic screening of neurexin [ 20 ], a Cysteine-Rich Region (CRR) derived from the N-terminal CRR of cerebellin [ 21 ], a Neurexide (NRX), a complex of neurexin and peptide [ 22 ], and Neurexin Binding Sites (NBS) derived from the NBS of neuroxophilin [ 23 ] for which an affinity for neurexin had already been reported ( Table 1 ). The characteristics of the prepared LPs are summarized in Table 2 .…”

Proteins secreted by brain arteriolar smooth muscle cells are instructive for neural development

“…4b). These pathways are commonly involved in regulating neurogenesis, neuritogenesis, neurite outgrowth, and cell survival processes [25][26][27][28][29]. There was no obvious enrichment of downregulated gene pathways.…”