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

• Published in: Neuron (Cambridge, Mass.) Vol. 98; no. 1; pp. 127 - 141.e7
• Main Authors: Vuong, Celine K., Wei, Weizheng, Lee, Ji-Ann, Lin, Chia-Ho, Damianov, Andrey, de la Torre-Ubieta, Luis, Halabi, Reem, Otis, Klara Olofsdotter, Martin, Kelsey C., O’Dell, Thomas J., Black, Douglas L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.04.2018; Elsevier Limited
• Subjects: 3' Untranslated regions; Animals; Autism; Brain; Cells, Cultured; Datasets; E/I balance; Epilepsy; Excitability; Female; Gene expression; inhibitory synaptic transmission; Interneurons; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; microRNA-9; miRNA; Neural Inhibition - physiology; Neurons; Neurons - chemistry; Neurons - metabolism; Phenotypes; posttranscriptional regulation; Proteins; Rbfox1; Ribonucleic acid; RNA; RNA Splicing Factors - analysis; RNA Splicing Factors - deficiency; RNA Splicing Factors - physiology; RNA-binding protein; Rodents; Seizures; SNARE Proteins - analysis; SNARE Proteins - biosynthesis; Software; Synaptic transmission; Synaptic Transmission - physiology; Vamp1; Vesicle-Associated Membrane Protein 1 - analysis; Vesicle-Associated Membrane Protein 1 - biosynthesis; Rbfox1; posttranscriptional regulation; RNA-binding protein; inhibitory synaptic transmission; E/I balance; Vamp1; microRNA-9
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.03.008

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. [Display omitted] •Cytoplasmic Rbfox1 post-transcriptionally regulates Vamp1 expression•Rbfox1 binding in the Vamp1 3′ UTR antagonizes miR9-mediated repression•Vamp1 is an inhibitory neuron-specific vSNARE enriched in PV+ interneurons•Vamp1 re-expression rescues the physiological defect of the Rbfox1 knockout Regulation of Vamp1 expression in inhibitory neurons by cytoplasmic Rbfox1 is required for proper inhibitory synaptic transmission and E/I balance. Restoring Vamp1 levels in Rbfox1 cKO inhibitory neurons is sufficient to rescue physiological defects.