Excitation/inhibition balance is critical for optimal brain function, yet the mechanisms underlying the tuning of inhibition from different populations of inhibitory neurons are unclear. Here, we found evidence for two distinct pathways through which excitatory neurons cell-autonomously modulate inhibitory synapses. Synapses from parvalbumin-expressing interneurons onto hippocampal pyramidal neurons are regulated by neuronal firing, signaling through L-type calcium channels. Synapses from somatostatin-expressing interneurons are regulated by NMDA receptors, signaling through R-type calcium channels. Thus, excitatory neurons can cell-autonomously regulate their inhibition onto different subcellular compartments through their input (glutamatergic signaling) and their output (firing). We found that in both the regulation of parvalbumin synapses by action potentials, and the regulation of somatostatin synapses by NMDA receptors represent alterations in the number of functional synapses.

Separately, little is known regarding whether synapses formed by somatostatin and parvalbumin interneurons onto pyramidal neurons are composed of different sets of post-synaptic components. Here, we found that while somatostatin and parvalbumin synapses onto excitatory neurons are both dependent on a common set of post-synaptic proteins, including gephyrin, collybistin, and neuroligin-2, somatostatin synapses are selectively impacted by neuroligin-3. Decreasing neuroligin-3 expression selectively decreases inhibition from somatostatin interneurons, and overexpression of neuroligin-3 selectively enhances somatostatin inhibition. Together, these results provide evidence that excitatory neurons can selectively regulate two distinct sets of inhibitory synapses.