Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1

Celine K Vuong; Weizheng Wei; Ji-Ann Lee; Chia-Ho Lin; Andrey Damianov; Luis de la Torre-Ubieta; Reem Halabi; Klara Olofsdotter Otis; Kelsey C Martin; Thomas J O'Dell; Douglas L Black

doi:10.1016/j.neuron.2018.03.008

Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1

Neuron. 2018 Apr 4;98(1):127-141.e7. doi: 10.1016/j.neuron.2018.03.008.

Authors

Affiliations

¹ Molecular Biology Interdepartmental Doctoral Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dougb@microbio.ucla.edu.

Abstract

Dysfunction of the neuronal RNA binding protein RBFOX1 has been linked to epilepsy and autism spectrum disorders. Rbfox1 loss in mice leads to neuronal hyper-excitability and seizures, but the physiological basis for this is unknown. We identify the vSNARE protein Vamp1 as a major Rbfox1 target. Vamp1 is strongly downregulated in Rbfox1 Nes-cKO mice due to loss of 3' UTR binding by RBFOX1. Cytoplasmic Rbfox1 stimulates Vamp1 expression in part by blocking microRNA-9. We find that Vamp1 is specifically expressed in inhibitory neurons, and that both Vamp1 knockdown and Rbfox1 loss lead to decreased inhibitory synaptic transmission and E/I imbalance. Re-expression of Vamp1 selectively within interneurons rescues the electrophysiological changes in the Rbfox1 cKO, indicating that Vamp1 loss is a major contributor to the Rbfox1 Nes-cKO phenotype. The regulation of interneuron-specific Vamp1 by Rbfox1 provides a paradigm for broadly expressed RNA-binding proteins performing specialized functions in defined neuronal subtypes.

Keywords: E/I balance; RNA-binding protein; Rbfox1; Vamp1; inhibitory synaptic transmission; microRNA-9; posttranscriptional regulation.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Female
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neural Inhibition / physiology*
Neurons / chemistry
Neurons / metabolism*
RNA Splicing Factors / analysis
RNA Splicing Factors / deficiency
RNA Splicing Factors / physiology*
SNARE Proteins / analysis
SNARE Proteins / biosynthesis
Synaptic Transmission / physiology*
Vesicle-Associated Membrane Protein 1 / analysis
Vesicle-Associated Membrane Protein 1 / biosynthesis*

Substances

RNA Splicing Factors
Rbfox1 protein, mouse
SNARE Proteins
Vesicle-Associated Membrane Protein 1
vesicle-associated membrane protein 1, mouse

Abstract

Publication types

MeSH terms

Substances

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