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Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy.

ABSTRACT: Recent studies have identified the leucine rich repeat protein LRRTM2 as a post-synaptic ligand of Neurexins. Neurexins also bind the post-synaptic adhesion molecules, Neuroligins. All three families of genes have been implicated in the etiologies of neurodevelopmental disorders, specifically autism spectrum disorders and schizophrenia. Does the binding promiscuity of Neurexins now suggest complex cooperativity or redundancy at the synapse? While recent studies in primary neuronal cultures and also systematic extracellular protein interaction screens suggest summative effects of these systems, we propose that studying these interactions in the developing zebrafish embryo or larvae may shed more light on their functions during synaptogenesis in vivo. These gene families have recently been extensively characterized in zebrafish, demonstrating high sequence conservation with the human genes. The simpler circuitry of the zebrafish, together with the characterization of the expression patterns down to single, identifiable neurons and the ability to knock-down or over-express multiple genes in a rapid way lend themselves to dissecting complex interaction pathways. Furthermore, the capability of performing high-throughput drug screens suggests that these small vertebrates may prove extremely useful in identifying pharmacological approaches to treating autism spectrum disorders.

SUBMITTER: Wright GJ

PROVIDER: S-EPMC3066302 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy.

Wright Gavin J GJ Washbourne Philip P

Journal of neurochemistry 20110119 5

Recent studies have identified the leucine rich repeat protein LRRTM2 as a post-synaptic ligand of Neurexins. Neurexins also bind the post-synaptic adhesion molecules, Neuroligins. All three families of genes have been implicated in the etiologies of neurodevelopmental disorders, specifically autism spectrum disorders and schizophrenia. Does the binding promiscuity of Neurexins now suggest complex cooperativity or redundancy at the synapse? While recent studies in primary neuronal cultures and a ...[more]

PMID: 21155806

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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, neuroligins and LRRTMs: synaptic adhesion getting fishy.

Publications

Neurexins, neuroligins and LRRTMs: synaptic adhesion getting fishy.

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