title: Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress.
abstract: In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events.
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 bli@cshl.edu zperova@mrc-lmb.cam.ac.uk.
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Perova
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724.
authors.forename: Kristen
authors.identifier: http://orcid.org/0000-0001-5698-0093
authors.initials: K
authors.lastname: Delevich
authors.affiliation: Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 bli@cshl.edu zperova@mrc-lmb.cam.ac.uk.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D003863:Depression / Q000473:pathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004558:Electric Stimulation; D006380:Helplessness, Learned; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007395:Interneurons / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000473:pathology*; D011930:Reaction Time; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000209:etiology / Q000473:pathology*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
chemical_list: D008164:Luminescent Proteins; D010320:Parvalbumins; D043588:Receptor, Muscarinic M4; C045073:Cre recombinase; D019426:Integrases
keywords: depression; learned helplessness; medial prefrontal cortex; parvalbumin interneuron; stress; synapse