Clptm1 Limits Forward Trafficking of GABA_A Receptors to Scale Inhibitory Synaptic Strength.

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

KEYWORDS: {{ getKeywords(articleDetailText.words) }}