2. Academic Validation
  3. Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength

Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength

  • Neuron. 2018 Feb 7;97(3):596-610.e8. doi: 10.1016/j.neuron.2017.12.038.
Yuan Ge 1,  Yunhee Kang 1,  Robert M Cassidy 1,  Kyung-Mee Moon 2,  Renate Lewis 3,  Rachel O L Wong 4,  Leonard J Foster 2,  Ann Marie Craig 5
Affiliations

Affiliations

  • 1 Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
  • 2 Department of Biochemistry and Molecular Biology and Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • 3 Department of Anatomy and Neurobiology, Washington University, St. Louis, MO 63110, USA.
  • 4 Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
  • 5 Djavad Mowafaghian Centre for Brain Health and Department of Psychiatry, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: [email protected].
PMID: 29395912 DOI: 10.1016/j.neuron.2017.12.038
Abstract

In contrast with numerous studies of glutamate receptor-associated proteins and their involvement in the modulation of excitatory synapses, much less is known about mechanisms controlling postsynaptic GABAA receptor (GABAAR) numbers. Using tandem affinity purification from tagged GABAAR γ2 subunit transgenic mice and proteomic analysis, we isolated several GABAAR-associated proteins, including Cleft lip and palate transmembrane protein 1 (Clptm1). Clptm1 interacted with all GABAAR subunits tested and promoted GABAAR trapping in the endoplasmic reticulum. Overexpression of Clptm1 reduced GABAAR-mediated currents in a recombinant system, in cultured hippocampal neurons, and in brain, with no effect on glycine or AMPA receptor-mediated currents. Conversely, knockdown of Clptm1 increased phasic and tonic inhibitory transmission with no effect on excitatory synaptic transmission. Furthermore, altering the expression level of Clptm1 mimicked activity-induced inhibitory synaptic scaling. Thus, in complement to Other GABAAR-associated proteins that promote receptor surface expression, Clptm1 limits GABAAR forward trafficking and regulates inhibitory homeostatic plasticity.

Keywords

Clptm1; GABA receptor-associated protein; GABAA receptor; GABAergic transmission; homeostasis; inhibitory synapse; receptor trafficking; synaptic scaling; tonic inhibition.

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