Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability

Khyobeni Mozhui, Rose Marie Karlsson, Thomas L. Kash, Jessica Ihne, Maxine Norcross, Sachin Patel, Mollee R. Farrell, Elizabeth E. Hill, Carolyn Graybeal, Kathryn P. Martin, Marguerite Camp, Paul J. Fitzgerald, Daniel C. Ciobanu, Rolf Sprengel, Masayoshi Mishina, Cara L. Wellman, Danny G. Winder, Robert Williams, Andrew Holmes

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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 (∼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.

Original languageEnglish (US)
Pages (from-to)5357-5367
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number15
DOIs
StatePublished - Apr 14 2010

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Amygdala
Glutamic Acid
Gene Expression
Anxiety
N-Methyl-D-Aspartate Receptors
Neurons
Dendritic Spines
Inbred Strains Mice
Neuronal Plasticity
AMPA Receptors
Glutamate Receptors
Prefrontal Cortex
Synaptic Transmission
Genes
Hippocampus
Depression
Phenotype
Light

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. / Mozhui, Khyobeni; Karlsson, Rose Marie; Kash, Thomas L.; Ihne, Jessica; Norcross, Maxine; Patel, Sachin; Farrell, Mollee R.; Hill, Elizabeth E.; Graybeal, Carolyn; Martin, Kathryn P.; Camp, Marguerite; Fitzgerald, Paul J.; Ciobanu, Daniel C.; Sprengel, Rolf; Mishina, Masayoshi; Wellman, Cara L.; Winder, Danny G.; Williams, Robert; Holmes, Andrew.

In: Journal of Neuroscience, Vol. 30, No. 15, 14.04.2010, p. 5357-5367.

Research output: Contribution to journalArticle

Mozhui, K, Karlsson, RM, Kash, TL, Ihne, J, Norcross, M, Patel, S, Farrell, MR, Hill, EE, Graybeal, C, Martin, KP, Camp, M, Fitzgerald, PJ, Ciobanu, DC, Sprengel, R, Mishina, M, Wellman, CL, Winder, DG, Williams, R & Holmes, A 2010, 'Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability', Journal of Neuroscience, vol. 30, no. 15, pp. 5357-5367. https://doi.org/10.1523/JNEUROSCI.5017-09.2010
Mozhui, Khyobeni ; Karlsson, Rose Marie ; Kash, Thomas L. ; Ihne, Jessica ; Norcross, Maxine ; Patel, Sachin ; Farrell, Mollee R. ; Hill, Elizabeth E. ; Graybeal, Carolyn ; Martin, Kathryn P. ; Camp, Marguerite ; Fitzgerald, Paul J. ; Ciobanu, Daniel C. ; Sprengel, Rolf ; Mishina, Masayoshi ; Wellman, Cara L. ; Winder, Danny G. ; Williams, Robert ; Holmes, Andrew. / Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 15. pp. 5357-5367.
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AU - Norcross, Maxine

AU - Patel, Sachin

AU - Farrell, Mollee R.

AU - Hill, Elizabeth E.

AU - Graybeal, Carolyn

AU - Martin, Kathryn P.

AU - Camp, Marguerite

AU - Fitzgerald, Paul J.

AU - Ciobanu, Daniel C.

AU - Sprengel, Rolf

AU - Mishina, Masayoshi

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AU - Williams, Robert

AU - Holmes, Andrew

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