Identification of an elaborate complex mediating postsynaptic inhibition.
Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. The composition of the inhibitory postsynapse and the mechanistic basis of its regulation, however, remain poorly understood. We used an in vivo chemico-genetic proximity-labeling approach to discover inhibitory postsynaptic proteins. Quantitative mass spectrometry not only recapitulated known inhibitory postsynaptic proteins but also revealed a large network of new proteins, many of which are either implicated in neurodevelopmental disorders or are of unknown function. Clustered regularly interspaced short palindromic repeats (CRISPR) depletion of one of these previously uncharacterized proteins, InSyn1, led to decreased postsynaptic inhibitory sites, reduced the frequency of miniature inhibitory currents, and increased excitability in the hippocampus. Our findings uncover a rich and functionally diverse assemblage of previously unknown proteins that regulate postsynaptic inhibition and might contribute to developmental brain disorders.
The Department of Cell Biology, Duke University Medical School, Durham, NC 27703, USA.
Akiyoshi
A
Uezu
The Department of Cell Biology, Duke University Medical School, Durham, NC 27703, USA.
Daniel J
DJ
Kanak
The Department of Cell Biology, Duke University Medical School, Durham, NC 27703, USA.
Tyler W A
TW
Bradshaw
The Department of Cell Biology, Duke University Medical School, Durham, NC 27703, USA. Duke Proteomics and Metabolomics Shared Resource and Duke Center for Genomic and Computational Biology, Duke University Medical School, Durham, NC 27703, USA.
Erik J
EJ
Soderblom
The Department of Cell Biology, Duke University Medical School, Durham, NC 27703, USA.
Christina M
CM
Catavero
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA. Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Alain C
AC
Burette
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA. Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Richard J
RJ
Weinberg
The Department of Cell Biology, Duke University Medical School, Durham, NC 27703, USA. The Department of Neurobiology, Duke University Medical School, Durham, NC 27703, USA. scott.soderling@duke.edu.
Scott H
SH
Soderling
D000818:Animals; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D006624:Hippocampus / Q000378:metabolism*; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009433:Neural Inhibition; D057907:Post-Synaptic Density / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020543:Proteome; C073441:gephyrin