Article
Proteolytic Processing of Neurexins by Presenilins Sustains Synaptic Vesicle Release
Author/s | Servián Morilla, Emilia
Robles Lanuza, Estefanía Sánchez Hidalgo, Ana Carmen Camacho García, Rafael J. Páez Gómez, Juan A. Mavillard Saborido, Fabiola Saura, Carlos A. Martinez-Mir, Amalia Gómez Scholl, Francisco Manuel |
Department | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica |
Publication Date | 2018-01-24 |
Deposit Date | 2024-07-30 |
Published in |
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Abstract | 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 ... 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. |
Funding agencies | European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Junta de Andalucía Ministerio de Economía y Competitividad (MINECO). España |
Project ID. | BFU2015-71464-R |
Citation | Servián Morilla, E., Robles Lanuza, E., Sánchez Hidalgo, A.C., Camacho García, R.J., Páez Gómez, J.A., Mavillard Saborido, F.,...,Gómez Scholl, F.M. (2018). Proteolytic Processing of Neurexins by Presenilins Sustains Synaptic Vesicle Release. The Journal of Neuroscience, 38 (4), 901-917. https://doi.org/10.1523/JNEUROSCI.1357-17.2017. |
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