The alpha1 subunit of the GABA(A) receptor modulates fear learning and plasticity in the lateral amygdala.

Synaptic plasticity in the amygdala is essential for emotional learning. Fear conditioning, for example, depends on changes in excitatory transmission that occur following NMDA receptor activation and AMPA receptor modification in this region. The role of these and other glutamatergic mechanisms have been studied extensively in this circuit while relatively little is known about the contribution of inhibitory transmission. The current experiments addressed this issue by examining the role of the GABA(A) receptor subunit alpha1 in fear learning and plasticity. We first confirmed previous findings that the alpha1 subunit is highly expressed in the lateral nucleus of the amygdala. Consistent with this observation, genetic deletion of this subunit selectively enhanced plasticity in the lateral amygdala and increased auditory fear conditioning. Mice with selective deletion of alpha1 in excitatory cells did not exhibit enhanced learning. Finally, infusion of a alpha1 receptor antagonist into the lateral amygdala selectively impaired auditory fear learning. Together, these results suggest that inhibitory transmission mediated by alpha1-containing GABA(A) receptors plays a critical role in amygdala plasticity and fear learning

Acute Stress Induces Contrasting Changes in AMPA Receptor Subunit Phosphorylation within the Prefrontal Cortex, Amygdala and Hippocampus

Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation is involved with these stress effects. Using an acute inescapable stress protocol with rats, we found opposite effects on AMPA receptor phosphorylation in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) compared to the amygdala and ventral hippocampus (VH). After stress, the phosphorylation of Ser831-GluA1 was markedly decreased in the mPFC and DH, whereas the phosphorylation of Ser845-GluA1 was increased in the amygdala and VH. Stress also modulated the GluA2 subunit with a decrease in the phosphorylation of both Tyr876-GluA2 and Ser880-GluA2 residues in the amygdala, and an increase in the phosphorylation of Ser880-GluA2 in the mPFC. These results demonstrate that exposure to acute stress causes subunit-specific and region-specific changes in glutamatergic transmission, which likely lead to the reduced synaptic efficacy in the mPFC and DH and augmented activity in the amygdala and VH. In addition, these findings suggest that modifications of glutamate receptor phosphorylation could mediate the disruptive effects of stress on cognition. They also provide a means to reconcile the contrasting effects that stress has on synaptic plasticity in these regions. Taken together, the results provide support for a brain region-oriented approach to therapeutics

Phosphorylation states at multiple AMPAR subunits after acute stress.

<p>Immunoblots and histograms of the ratio between the phosphorylated form and total amount of the protein (white bars: no stress group, cross hatched bars: stress group). In the mPFC (A), stress decreased Ser831-GluA1 phosphorylation (p<0.05) and increased Ser880-GluA2 phosphorylation (p<0.05). In the amygdala (B), stress increased Ser845-GluA1 phosphorylation (p<0.05) and decreased Tyr876-GluA2 and Ser880-GluA2 phosphorylation (p<0.05. In the DH (C), stress decreased Ser831-GluA1 phosphorylation (p<0.05). In the VH (D), stress increased Ser845-GluA1 phosphorylation (p<0.05) and decreased Ser880-GluA2 phosphorylation (p<0.05). Immunoblots (100 kDa) illustrate the phosphorylated form of the protein (left: control, right: stress). The number of animals per group is 10 for controls and 11 for stress. Unpaired, two-tailed, Student's T-test. *, p<0.05, compared with the corresponding control group.</p

Summary of changes in AMPAR phosphorylation of GluA1 and GluA2 subunits after stress in the four regions studied.

<p>Summary of changes in AMPAR phosphorylation of GluA1 and GluA2 subunits after stress in the four regions studied.</p