Developing breakthrough psychiatric treatments by modulating G protein-coupled receptors on prefrontal cortex somatostatin interneurons

Abstract

Prefrontal cortex (PFC) interneurons expressing the neuropeptide somatostatin (SST-INs) are implicated in the etiology of several psychiatric diseases [1, 2]. Emergent findings from animal models now demonstrate that PFC SST-INs are essential in orchestrating adaptive affective behaviors and that aberrant SST-IN signaling is involved in maladaptive emotive responses. An exemplary recent study by Cummings and Clem revealed that synaptic potentiation through SST-IN microcircuits mediates associative fear learning in male mice [3], suggesting shared or similar molecular mechanisms likely contribute to affective behavioral alterations in diseaserelevant models. Indeed, studies from our laboratories have revealed that stress and chronic alcohol consumption alter SST-IN function [4, 5]. These studies, along with others linking SST-IN function with generalized fear, chronic pain, and acute psychosis, provide great motivation for developing translational approaches to manipulate SST-IN activity. Modulating PFC SST-INs may therefore provide avenues towards ameliorating anxious and depressive symptoms in diseases like major depressive disorder, anxiety disorders, and substance and alcohol use disorders. Nonetheless, continuing to probe how exactly SST-IN modulation affects PFC circuit function remains a key question for continued research. Recent findings suggest some SST-INs (i.e., X94 cells) inhibit other types of INs to facilitate cortical disinhibition [3], revising and updating the canonical SST-IN dendritic inhibition motif. Thus, positive and negative modulation of distinct subclasses of SST-INs harbors great diversity in opportunities for developing new SST-IN-directed treatments to sculpt PFC circuit function (Fig. 1).