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A de novo missense mutation in synaptotagmin-1 associated with neurodevelopmental disorder desynchronizes neurotransmitter release.
van Boven, Maaike A; Mestroni, Marta; Zwijnenburg, Petra J G; Verhage, Matthijs; Cornelisse, L Niels.
Afiliación
  • van Boven MA; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, 1081 HV, Amsterdam, The Netherlands.
  • Mestroni M; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, 1081 HV, Amsterdam, The Netherlands.
  • Zwijnenburg PJG; Department of Human Genetics, Amsterdam UMC, 1105 AZ, Amsterdam, The Netherlands.
  • Verhage M; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, 1081 HV, Amsterdam, The Netherlands.
  • Cornelisse LN; Department of Functional Genomics and Department of Human Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam UMC-Location VUmc, 1081 HV, Amsterdam, The Netherlands.
Mol Psychiatry ; 29(6): 1798-1809, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38321119
ABSTRACT
Synaptotagmin-1 (Syt1) is a presynaptic calcium sensor with two calcium binding domains, C2A and C2B, that triggers action potential-induced synchronous neurotransmitter release, while suppressing asynchronous and spontaneous release. We identified a de novo missense mutation (P401L) in the C2B domain in a patient with developmental delay and autistic symptoms. Expressing the orthologous mouse mutant (P400L) in cultured Syt1 null mutant neurons revealed a reduction in dendrite outgrowth with a proportional reduction in synapses. This was not observed in single Syt1PL-rescued neurons that received normal synaptic input when cultured in a control network. Patch-clamp recordings showed that spontaneous miniature release events per synapse were increased more than 500% in Syt1PL-rescued neurons, even beyond the increased rates in Syt1 KO neurons. Furthermore, action potential-induced asynchronous release was increased more than 100%, while synchronous release was unaffected. A similar shift to more asynchronous release was observed during train stimulations. These cellular phenotypes were also observed when Syt1PL was overexpressed in wild type neurons. Our findings show that Syt1PL desynchronizes neurotransmission by increasing the readily releasable pool for asynchronous release and reducing the suppression of spontaneous and asynchronous release. Neurons respond to this by shortening their dendrites, possibly to counteract the increased synaptic input. Syt1PL acts in a dominant-negative manner supporting a causative role for the mutation in the heterozygous patient. We propose that the substitution of a rigid proline to a more flexible leucine at the bottom of the C2B domain impairs clamping of release by interfering with Syt1's primary interface with the SNARE complex. This is a novel cellular phenotype, distinct from what was previously found for other SYT1 disease variants, and points to a role for spontaneous and asynchronous release in SYT1-associated neurodevelopmental disorder.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transmisión Sináptica / Neurotransmisores / Mutación Missense / Sinaptotagmina I / Trastornos del Neurodesarrollo / Neuronas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transmisión Sináptica / Neurotransmisores / Mutación Missense / Sinaptotagmina I / Trastornos del Neurodesarrollo / Neuronas Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Mol Psychiatry Asunto de la revista: BIOLOGIA MOLECULAR / PSIQUIATRIA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido