title: Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.
abstract: Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Khyobeni
authors.initials: K
authors.lastname: Mozhui
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Karlsson
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Kash
authors.forename: Jessica
authors.initials: J
authors.lastname: Ihne
authors.forename: Maxine
authors.initials: M
authors.lastname: Norcross
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
authors.forename: Mollee R
authors.initials: MR
authors.lastname: Farrell
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Hill
authors.forename: Carolyn
authors.initials: C
authors.lastname: Graybeal
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Martin
authors.forename: Marguerite
authors.initials: M
authors.lastname: Camp
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fitzgerald
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Ciobanu
authors.forename: Rolf
authors.initials: R
authors.lastname: Sprengel
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.forename: Cara L
authors.initials: CL
authors.lastname: Wellman
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D049229:Dendritic Spines / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D017397:Prefrontal Cortex / Q000503:physiopathology; D018091:Receptors, AMPA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical; D013045:Species Specificity; D013315:Stress, Psychological / Q000235:genetics* / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D018698:Glutamic Acid; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate
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