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 GABA receptor (GABAR) numbers. Using tandem affinity purification from tagged GABAR γ2 subunit transgenic mice and proteomic analysis, we isolated several GABAR-associated proteins, including Cleft lip and palate transmembrane protein 1 (Clptm1). Clptm1 interacted with all GABAR subunits tested and promoted GABAR trapping in the endoplasmic reticulum. Overexpression of Clptm1 reduced GABAR-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 GABAR-associated proteins that promote receptor surface expression, Clptm1 limits GABAR forward trafficking and regulates inhibitory homeostatic plasticity.
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