An Essential Role for the Tetraspanin LHFPL4 in the Cell-Type-Specific Targeting and Clustering of Synaptic GABAReceptors

Elizabeth C Davenport, Valentina Pendolino, Georgina Kontou, Thomas P McGee, David F Sheehan, Guillermo López-Doménech, Mark Farrant, Josef T Kittler

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Inhibitory synaptic transmission requires the targeting and stabilization of GABAAreceptors (GABAARs) 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 GABAAR clustering in hippocampal pyramidal neurons. LHFPL4 interacts tightly with GABAAR subunits and is selectively enriched at inhibitory synapses. In LHFPL4 knockout mice, there is a dramatic cell-type-specific reduction in GABAAR and gephyrin clusters and an accumulation of large intracellular gephyrin aggregates in vivo. While GABAARs 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.

Original languageEnglish
Pages (from-to)70-83
Number of pages14
JournalCell Reports
Volume21
Issue number1
DOIs
Publication statusPublished - 3 Oct 2017

Keywords / Materials (for Non-textual outputs)

  • Journal Article

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