Acute restraint stress redirects prefrontal cortex circuit function through mGlu5 receptor plasticity on somatostatin-expressing interneurons

Neuron. 2022 Mar 16;110(6):1068-1083.e5. doi: 10.1016/j.neuron.2021.12.027. Epub 2022 Jan 18.


Inhibitory interneurons orchestrate prefrontal cortex (PFC) activity, but we have a limited understanding of the molecular and experience-dependent mechanisms that regulate synaptic plasticity across PFC microcircuits. We discovered that mGlu5 receptor activation facilitates long-term potentiation at synapses from the basolateral amygdala (BLA) onto somatostatin-expressing interneurons (SST-INs) in mice. This plasticity appeared to be recruited during acute restraint stress, which induced intracellular calcium mobilization within SST-INs and rapidly potentiated postsynaptic strength onto SST-INs. Restraint stress and mGlu5 receptor activation each augmented BLA recruitment of SST-IN phasic feedforward inhibition, shunting information from other excitatory inputs, including the mediodorsal thalamus. Finally, studies using cell-type-specific mGlu5 receptor knockout mice revealed that mGlu5 receptor function in SST-expressing cells is necessary for restraint stress-induced changes to PFC physiology and related behaviors. These findings provide new insights into interneuron-specific synaptic plasticity mechanisms and suggest that SST-IN microcircuits may be promising targets for treating stress-induced psychiatric diseases.

Keywords: Ca(2+)-permeable AMPA receptor; DART; GABA; GPCR; GluA2-lacking AMPA receptor; antidepressant; metabotropic glutamate receptor; motivation; optogenetics; working memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Interneurons* / physiology
  • Long-Term Potentiation
  • Mice
  • Neuronal Plasticity / physiology
  • Prefrontal Cortex / physiology
  • Somatostatin* / metabolism
  • Synapses / physiology


  • Somatostatin