Tomosyn-2 is required for normal motor performance in mice and sustains neurotransmission at motor endplates

Geerts, Cornelia J.; Plomp, Jaap J.; Koopmans, Bastijn; Loos, Maarten; Pijl, Elizabeth M. van der; Valk, Martin A. van der; Verhage, Matthijs; Groffen, Alexander J.

doi:10.1007/s00429-014-0766-0

Cited by 23 publications

(27 citation statements)

References 37 publications

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“…Some CNVs affected genes that are specifically expressed in the brain, and/or constrained against deletions and loss of function mutations, (Figure and Supplementary Information Appendix S1: list “constrains and expression”), identifying them as novel candidate genes for impulsive behavior. These genes included FBXL16 , PHACTR3, CDH20, FAM155A , DOK6, NKAIN2 , STXBP5L , or PCDH9 , UNC13C , and DPP10, C7orf26 , FSD1 , GLT8D1 , or GNL3. Other candidate genes included DNAJC15 and UBE2V2.…”

Section: Resultsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

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The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome‐wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age ≥ 18 years, an ICD‐10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single‐nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2‐25 times). Many of these genes are associated with autosomal dominant or X‐linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.

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Section: Resultsmentioning

confidence: 99%

Rare copy number variation in extremely impulsively violent males

Vevera

Zarrei

Hartmannová

et al. 2018

Genes Brain and Behavior

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“…The impaired γ-oscillations registered in the Slm2 KO brain may also be impacted by altered Tomosyn2 splicing that could affect Tomosyn2 protein stability (Williams et al., 2011). Tomosyn2 controls acetyl choline release from cholinergic nerve terminals (Geerts et al., 2015) and acetylcholine (ACh) is known to induce persistent γ-oscillations in the hippocampus (Picciotto et al., 2012). LysoPLD/ATX encodes one of the major enzymes involved in synthesis of lysophospatidic acid (LPA), a molecule with a key signaling role controlling both excitatory and inhibitory synapse functions (García-Morales et al., 2015, Vogt et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

et al. 2016

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SummaryThe brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.

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“…828–983; SySy; 1:1000) and anti-VCP (K331; Sugita and Südhof, 2000; 1:1000). Tomosyn-1 and tomosyn-2 antibody specificity was validated using HEK293 cell lysates overexpressing tomosyn and brain lysates from Tom2 KO/KO mice [39] and using immunocytochemistry on wild type and Tom1 KO/KO cultured hippocampal neurons (S1 Fig). For immunocytochemistry, primary anti-MAP2 antibody (Abcam, Cambridge, UK; 1:1000) and SMI-312 antibody (Covance, Princeton, NJ; 1:1000) were used for detection of respectively dendrites and axons.…”

Section: Methodsmentioning

confidence: 99%

Tomosyn associates with secretory vesicles in neurons through its N- and C-terminal domains

et al. 2017

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The secretory pathway in neurons requires efficient targeting of cargos and regulatory proteins to their release sites. Tomosyn contributes to synapse function by regulating synaptic vesicle (SV) and dense-core vesicle (DCV) secretion. While there is large support for the presynaptic accumulation of tomosyn in fixed preparations, alternative subcellular locations have been suggested. Here we studied the dynamic distribution of tomosyn-1 (Stxbp5) and tomosyn-2 (Stxbp5l) in mouse hippocampal neurons and observed a mixed diffuse and punctate localization pattern of both isoforms. Tomosyn-1 accumulations were present in axons and dendrites. As expected, tomosyn-1 was expressed in about 75% of the presynaptic terminals. Interestingly, also bidirectional moving tomosyn-1 and -2 puncta were observed. Despite the lack of a membrane anchor these puncta co-migrated with synapsin and neuropeptide Y, markers for respectively SVs and DCVs. Genetic blockade of two known tomosyn interactions with synaptotagmin-1 and its cognate SNAREs did not abolish its vesicular co-migration, suggesting an interplay of protein interactions mediated by the WD40 and SNARE domains. We hypothesize that the vesicle-binding properties of tomosyns may control the delivery, pan-synaptic sharing and secretion of neuronal signaling molecules, exceeding its canonical role at the plasma membrane.

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Tomosyn-2 is required for normal motor performance in mice and sustains neurotransmission at motor endplates

Cited by 23 publications

References 37 publications

Rare copy number variation in extremely impulsively violent males

Rare copy number variation in extremely impulsively violent males

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

Tomosyn associates with secretory vesicles in neurons through its N- and C-terminal domains

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