Abstract
Inhibitory synaptic transmission requires the targeting and stabilization of GABA(A) receptors (GABA(A)Rs) at synapses. The mechanisms responsible remain poorly understood, and roles for transmembrane accessory proteins have not been established. Using molecular, imaging, and electrophysiological approaches, we identify the tetraspanin LHFPL4 as a critical regulator of postsynaptic GABA(A)R clustering in hippocampal pyramidal neurons. LHFPL4 interacts tightly with GABA(A)R subunits and is selectively enriched at inhibitory synapses. In LHFPL4 knockout mice, there is a dramatic cell-type-specific reduction in GABA(A)R and gephyrin clusters and an accumulation of large intracellular gephyrin aggregates in vivo. While GABA(A)Rs are still trafficked to the neuronal surface in pyramidal neurons, they are no longer localized at synapses, resulting in a profound loss of fast inhibitory postsynaptic currents. Hippocampal interneuron currents remain unaffected. Our results establish LHFPL4 as a synapse-specific tetraspanin essential for inhibitory synapse function and provide fresh insights into the molecular make-up of inhibitory synapses.