Strain Differences in Stress Responsivity Are Associated with Divergent Amygdala Gene Expression and Glutamate-Mediated Neuronal Excitability

Authors

Khyobeni Mozhui, University of Tennessee Health Science Center
Rose-Marie Karlsson, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Thomas L. Kash, Vanderbilt University School of Medicine
Jessica Ihne, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Maxine Norcross, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Sachin Patel, Vanderbilt University School of Medicine
Mollee R. Farrell, Indiana University
Elizabeth E. Hill, Indiana University
Carolyn Graybeal, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Kathryn P. Martin, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Marguerite Camp, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Paul J. Fitzgerald, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
Daniel C. Ciobanu, University of Nebraska-LincolnFollow
Rolf Sprengel, Max-Planck Institute for Medical Research
Masayoshi Mishina, University of Tokyo
Cara L. Wellman, Indiana University
Danny G. Winder, Vanderbilt University School of Medicine
Robert W. WIlliams, University of Tennessee Health Science Center
Andrew Holmes, National Institute on Alcohol Abuse and Alcoholism, National Institutes of HealthFollow

Document Type

Article

Date of this Version

2010

Citation

J. Neurosci., April 14, 2010, 30(15):5357–5367

Comments

Copyright 2010 the authors.

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.