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 (ϳ30%) 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.

The response of neuregulin 1 mutant mice to acute restraint stress

“…A similar phenomenon has been described in another mouse study [2]. Elevated exploration of open spaces has been interpreted as a strain-specific more active stress coping mechanism of C57BL/6J mice [22].…”

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

“…For instance, increased excitatory responses to glutamate and increased glutamatergic synaptic transmission. The increased excitatory response to glutamate could be caused by increased neuronal membrane excitability (Rosenkranz et al, 2010;Hetzel and Rosenkranz, 2014), increased function of NMDA or AMPA receptors (Adamec et al, 2005;Caudal et al, 2010;Mozhui et al, 2010;Suvrathan et al, 2014), reduced glutamatergic drive of GABAergic networks (Masneuf et al, 2014), or upregulation of glutamatergic receptors (Lei and Tejani-Butt, 2010;Gan et al, 2014). Increased glutamatergic synaptic transmission could be caused by increased glutamatergic inputs, as observed here and in other studies (Mitra et al, 2005;Vyas et al, 2006;Padival et al, 2013Padival et al, , 2015Suvrathan et al, 2014;Tsai et al, 2014).…”

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

“…The inbred mouse strains DBA/2 and BALB/c (both homozygous for the Tph2 allele 1473G) show increased anxiety-like behavior in comparison with C57BL/6, which are homozygous for the Tph2 1473C allele (Bouwknecht and Paylor, 2002;Griebel et al, 2000;Mozhui et al, 2010). Both DBA/2 and BALB/c strains are regarded as more stresssensitive compared with C57BL/6 because they show higher stress-induced increases in corticosterone concentration and increased anxiety-related behavior following chronic stress (Brinks et al, 2007;Mozhui et al, 2010;Shanks and Anisman, 1988).…”

“…Both DBA/2 and BALB/c strains are regarded as more stresssensitive compared with C57BL/6 because they show higher stress-induced increases in corticosterone concentration and increased anxiety-related behavior following chronic stress (Brinks et al, 2007;Mozhui et al, 2010;Shanks and Anisman, 1988). In addition, 5-HT synthesis, 5-HT tissue concentrations, and extracellular 5-HT levels were shown to be reduced in DBA/2 and BALB/c mice compared with C57Bl6/N (Calcagno et al, 2007;Isles et al, 2005;Jacobsen et al, 2008;Zhang et al, 2004).…”