GLUCOCORTICOID RECEPTOR AND PROTEIN RNA SYNTHESIS-DEPENDENT MECHANISMS UNDERLIE THE CONTROL OF SYNAPTIC PLASTICITY BY STRESS/

Learning and memory are exquisitely sensitive to behavioral stress, bu t the underlying mechanisms are still poorly understood. Because activ ity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as the hippocampus we hav e examined the means by which stress affects synaptic plasticity in th e CA1 region of the hippocampus of anesthetized rats, Inescapable beha vioral stress (placement on an elevated platform for 30 min) switched the direction of plasticity, favoring low frequency stimulation-induce d decreases in synaptic transmission (long-term depression, LTD), and opposing the induction of long-term potentiation by high frequency sti mulation, We have discovered that glucocorticoid receptor activation m ediates these effects of stress on LTD and longterm potentiation in a protein synthesis-dependent manner because they were prevented by the glucocorticoid receptor antagonist RU 38486 and the protein synthesis inhibitor emetine. Consistent with this, the ability of exogenously ap plied corticosterone in non-stressed rats to mimic the effects of stre ss on synaptic plasticity was also blocked by these agents, The enable ment of low frequency stimulation-induced LTD by both stress and exoge nous corticosterone was also blocked by the transcription inhibitor ac tinomycin D, Thus, naturally occurring synaptic plasticity is liable t o be reversed in stressful situations via glucocorticoid receptor acti vation and mechanisms dependent on the synthesis of new protein and RN A, This indicates that the modulation of hippocampus-mediated learning by acute inescapable stress requires glucocorticoid receptor-dependen t initiation of transcription and translation.