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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2022-03, Vol.110 (6), p.1068-1083.e5
• Main Authors: Joffe, Max E., Maksymetz, James, Luschinger, Joseph R., Dogra, Shalini, Ferranti, Anthony S., Luessen, Deborah J., Gallinger, Isabel M., Xiang, Zixiu, Branthwaite, Hannah, Melugin, Patrick R., Williford, Kellie M., Centanni, Samuel W., Shields, Brenda C., Lindsley, Craig W., Calipari, Erin S., Siciliano, Cody A., Niswender, Colleen M., Tadross, Michael R., Winder, Danny G., Conn, P. Jeffrey
• Format: Article
• Language: English
• Subjects: antidepressant; Ca2+-permeable AMPA receptor; DART; GABA; GluA2-lacking AMPA receptor; GPCR; metabotropic glutamate receptor; motivation; optogenetics; working memory
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.12.027

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. [Display omitted] •Restraint stress activates PFC SST-INs•Restraint stress enhances excitatory drive onto SST-INs and feedforward inhibition•mGlu5 receptors regulate LTP on SST-INs•SST-mGlu5−/− mice display unique stress-related behavioral adaptations Joffe et al. demonstrated that restraint stress rapidly potentiates excitatory transmission onto prefrontal cortex somatostatin interneurons in mice, biasing information processing toward amygdala-driven feedforward inhibition. The authors pinpoint metabotropic glutamate mGlu5 receptor plasticity on somatostatin interneurons as an essential mediator of microcircuit modifications and discrete behavioral adaptations following acute stress.