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Neurexins - versatile molecular platforms in the synaptic cleft.

ABSTRACT: Neurexins constitute a large family of synaptic organizers. Their extracellular domains protrude into the synaptic cleft where they can form transsynaptic bridges with different partners. A unique constellation of structural elements within their ectodomains enables neurexins to create molecular platforms within the synaptic cleft that permit a large portfolio of partners to be recruited, assembled and their interactions to be dynamically regulated. Neurexins and their partners are implicated in neuropsychiatric diseases including autism spectrum disorder and schizophrenia. Detailed understanding of the mechanisms that underlie neurexin interactions may in future guide the design of tools to manipulate synaptic connections and their function, in particular those involved in the pathogenesis of neuropsychiatric disease.

SUBMITTER: Rudenko G

PROVIDER: S-EPMC6592730 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Neurexins - versatile molecular platforms in the synaptic cleft.

Rudenko G G

Current opinion in structural biology 20190201

Neurexins constitute a large family of synaptic organizers. Their extracellular domains protrude into the synaptic cleft where they can form transsynaptic bridges with different partners. A unique constellation of structural elements within their ectodomains enables neurexins to create molecular platforms within the synaptic cleft that permit a large portfolio of partners to be recruited, assembled and their interactions to be dynamically regulated. Neurexins and their partners are implicated in ...[more]

PMID: 30831539

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Project description:Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by neurexins (Nrxns) and neuroligins (Nlgns) bidirectionally orchestrate the function of presynaptic and postsynaptic terminals. Previous studies have shown that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Nrxn C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding. Here, we characterized the synaptic consequences of the proteolytic processing of Nrxns in cultured hippocampal neurons from mice and rats of both sexes. We show that activation of presynaptic Nrxns with postsynaptic Nlgn1 or inhibition of ectodomain shedding in axonal Nrxn1-β increases presynaptic release at individual terminals, likely reflecting an increase in the number of functional release sites. Importantly, inactivation of PS inhibits presynaptic release downstream of Nrxn activation, leaving synaptic vesicle recruitment unaltered. Glutamate-receptor signaling initiates the activity-dependent generation of Nrxn-CTF, which accumulate at presynaptic terminals lacking PS function. The sole expression of Nrxn-CTF decreases presynaptic release and calcium flux, recapitulating the deficits due to loss of PS function. Our data indicate that inhibition of Nrxn processing by PS is deleterious to glutamatergic function.SIGNIFICANCE STATEMENT To gain insight into the role of presenilins (PS) in excitatory synaptic function, we address the relevance of the proteolytic processing of presynaptic neurexins (Nrxns) in glutamatergic differentiation. Using synaptic fluorescence probes in cultured hippocampal neurons, we report that trans-synaptic activation of Nrxns produces a robust increase in presynaptic calcium levels and neurotransmitter release at individual glutamatergic terminals by a mechanism that depends on normal PS activity. Abnormal accumulation of Nrxn C-terminal fragments resulting from impaired PS activity inhibits presynaptic calcium signal and neurotransmitter release, assigning synaptic defects to Nrxns as a specific PS substrate. These data may provide links into how loss of PS activity inhibits glutamatergic synaptic function in Alzheimer's disease patients.

Dataset Information

Neurexins - versatile molecular platforms in the synaptic cleft.

Publications

Neurexins - versatile molecular platforms in the synaptic cleft.

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