Together, the evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in mood disorders and that rescuing SST+ cell function via α5-PAM may represent a targeted therapeutic strategy. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions, α5-GABAA receptor positive allosteric modulators (α5-PAMs), achieved antidepressant-like effects. A causal link between SST+ cell dysfunction and symptom-related behaviors has been proposed based on rodent studies showing that chronic stress, a major risk factor for mood and anxiety disorders, induces a low SST+ GABA cellular phenotype across corticolimbic brain regions that lowering Sst, SST+ cell, or GABA functions induces depressive-/anxiety-like behaviors (a rodent behavioral construct collectively defined as “behavioral emotionality”) and that disinhibiting SST+ cells has antidepressant-like effects. The INs subtype distinct and microcircuit-based mechanism advances our understanding of the etiology of social fear and sheds light on developing future treatment of neuropsychiatric disorders associated with social fear.ĭeficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ GABA cells) are commonly reported in human studies of mood and anxiety disorder patients. Here, we review the rodent animal models of social fear, the prefrontal IN diversity, and their circuits with a particular emphasis on a novel disinhibitory microcircuit mediated by somatostatin-expressing INs in gating social fear behavior. Disinhibition, defined as a break in inhibition via interactions between IN subtypes that enhances the output of excitatory PNs, has recently been discovered to serve as an efficient strategy in cortical information processing.
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Prefrontal cortical functions are implemented by a finely wired microcircuit composed of excitatory principal neurons (PNs) and diverse subtypes of inhibitory interneurons (INs). With the development of appropriate animal models, growing studies start to unravel neuronal circuit mechanisms underlying social fear, and underscore a fundamental role of the prefrontal cortex (PFC). The pathological mechanism of SAD remains elusive and there are no specific and satisfactory therapeutic options currently available. Social fear and avoidance of social partners and social situations represent the core behavioral symptom of Social Anxiety Disorder (SAD), a prevalent psychiatric disorder worldwide. Figure 1B provided courtesy of Jean-Marc Fritschy. (C) Scheme of the extrasynaptic localization of α5 GABA A receptors on dendrites and dendritic spines of hippocampal pyramidal cells, representing the initial, tonic inhibitory control to incoming excitatory signals. High expression in hippocampus and cortical layer 5 is shown. (B) Immunohistochemical distribution of the α5 subunit of GABA A receptors in mouse brain with false color coding.
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ACh, acetylcholine CS, conditioned stimulus PV, parvalbumin VIP, vasoactive intestinal polypeptide. Blue color denotes the source of disinhibition, yellow color the inhibited interneurons, and green color the disinhibited pyramidal neurons.
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A circuit model is given for the cortical disinhibition elicited by an unconditioned stimulus (US) (footshock) in auditory Pavlovian fear learning (modified from 1). (A) Disinhibition refers to the selective and transient reduction of synaptic inhibition of a projection neuron due to suppression of interneuron firing by another population of interneurons.