Activation of group II metabotropic glutamate receptors induces long-term depression of synaptic transmission in the rat amygdala

An animal model most sensitive for measuring anticipatory anxiety is fear c onditioning, which is expressed by an enduring increase in synaptic strengt h in the amygdala. A converse view predicts that agents that induce long-te rm depression (LTD) of synaptic efficacy in the amygdala may be useful in t he amelioration of stress disorders. In the present study, we show that act ivation of group II metabotropic glutamate receptor (mGluR II) by (2S, 3S, 4S)-2-(carboxycyclopropyl) glycine (L-CCG) induces an LTD in the basolatera l amygdala neurons. The effect was concentration-dependent with a maximal i nhibition of similar to 30%. The induction of L-CCG LTD required concurrent synaptic activity, required presynaptic but not postsynaptic Ca2+ increase s, and was independent of NMDA receptors. L-CCG LTD was associated with an increase in the ratio of paired-pulse facilitation and was not occluded by low-frequency stimulation-induced LTD, suggesting that these two forms of L TD did not share a common underlying mechanism. After eliciting LTD with L-CCG, application of isoproterenol increased the synaptic responses back to its original baseline, demonstrating that chemic ally depressed synapses could be potentiated by another chemical. A selecti ve PKA inhibitor, KT 5720, by its own caused a depression of synaptic trans mission and blocked L-CCG LTD, presumably by mimicking and thereby occludin g any further depression. Together, these results suggest that L-CCG LTD is induced by presynaptically mGluR II-mediated inhibition of Ca2+-sensitive adenylyl cyclase, resulting in a decrease in cAMP formation and PKA activat ion, which leads to a long-lasting decrease in transmitter release.