Undergirding the study of these dynamic interactions are efforts to map the structural and functional connections between long-range inputs and mPFC interneurons. Indeed, work using trans-synaptic viral tracing, retrograde labelling, optogenetic stimulation, and whole-cell electrophysiology has revealed previously unappreciated specificity in the synaptic targeting and modulation of mPFC interneurons by inputs originating from disparate and intermingled neuronal populations (e.g., [3,4,5,6]). In one striking study, Sanchez-Bellot and colleagues [4] showed that a subset of projection neurons in superficial vHPC preferentially synapses onto diverse mPFC interneurons, whereas a subset in deeper vHPC preferentially targets pyramidal neurons and fast-spiking interneurons. This dissociable connectivity seems to underlie functional specificity, as activation of these parallel pathways promoted exploration and avoidance, respectively.

Emerging evidence further reveals that highly specialized input-interneuron connections in mPFC are remodeled by disease-relevant genetic insults and salient experience. In an elegant series of experiments, Joffe and colleagues [6] found that acute restraint stress in mice potentiated excitatory drive of basolateral amygdala inputs onto mPFC SST-INs, likely through a metabotropic glutamate receptor-5 (mGlu5)-dependent form of long-term potentiation. Further, this potentiation preferentially facilitated heterosynaptic inhibition of excitatory transmission at mediodorsal thalamus-derived inputs to mPFC pyramidal neurons. Genetic deletion of mGlu5 in SST-INs also prevented restraint stress-induced impairments in spatial working memory task performance. Collectively, these findings indicate that experience-induced plasticity at SST-INs can bias the routing of circuit-specific, behaviorally relevant information though mPFC.

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