Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network

Hippocampal network activity is generated by a complex interplay between excitatory pyramidal cells and inhibitory interneurons. Although much is known about the molecular properties of excitatory synapses on pyramidal cells, comparatively little is known about excitatory synapses on interneurons. Here, we show that conditional deletion of the postsynaptic cell adhesion molecule neuroligin-3 in parvalbumin interneurons causes a decrease in NMDA receptor-mediated postsynaptic currents and an increase in presynaptic glutamate release probability due to selectively impairing the inhibition of glutamate release by presynaptic Group III metabotropic glutamate receptors. As a result, the neuroligin-3 deletion altered network activity by reducing gamma oscillations and sharp wave ripples; changes associated with a decrease in extinction of contextual fear memories. These results demonstrate that neuroligin-3 specifies the properties of excitatory synapses on parvalbumin-containing interneurons by a retrograde trans-synaptic mechanism and suggest a novel molecular pathway whereby neuroligin-3 mutations contribute to neuropsychiatric disorders.