title: Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses.
abstract: Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, Baltimore, Maryland; Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, Maryland; and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Kvarta
authors.affiliation: Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland.
authors.forename: Keighly E
authors.initials: KE
authors.lastname: Bradbrook
authors.affiliation: Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Dantrassy
authors.affiliation: Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland.
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Bailey
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland; Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, Baltimore, Maryland; sthom003@umaryland.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000502:physiology; D003345:Corticosterone / Q000097:blood / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D065853:Spatial Learning; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: D018091:Receptors, AMPA; D003345:Corticosterone
keywords: anhedonia; depression; metyrapone; synaptic strength; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring glutamate receptor