The atypical adhesion GPCR ADGRA1 controls hippocampal inhibitory circuit function

Neural circuits contain a diverse array of inhibitory interneurons that control information processing. The cell surface receptors and signaling pathways that modulate cell-type-specific inhibitory function are unclear. Here, we identify the orphan G protein-coupled receptor (GPCR) ADGRA1 as essential for hippocampal PV inhibitory synaptic function. ADGRA1 is selectively enriched in hippocampal PV interneurons and localizes to a subset of synapses. ADGRA1 deletion in PV interneurons impairs intrinsic excitability and reduces inhibitory synaptic strength onto dentate gyrus granule cells. ADGRA1 engages several downstream G proteins, notably Gα13, a pathway important for the establishment of hippocampal PV interneuron synaptic networks. These results identify an orphan receptor pathway selective for fast-spiking PV neuron function and expand our understanding of the signaling mechanisms that establish hippocampal inhibitory circuits.