Studies of the cellular mechanisms underlying long-term depression in the amygdala

• Main Authors: Hui-Ching Lin, 林惠菁
• Other Authors: Po-Wu Gean
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/11212704611593286600

碩士 === 國立成功大學 === 藥理學研究所 === 88 === 英 文 摘 要 (Abstract in English) Clinically, the inability to eliminate fear and anxiety ranks as one of the major problems in psychiatry. The amygdala has been suggested to play important role in certain forms of neuroplasticity such as emotional memory and epilepsy. Two widely used animal models known to be related to the functions of amygdala are kindling and fear -potentiated startle. Both kindling and fear conditioning resulted in a sustained enhancement of excitatory synaptic transmission in the amygdala. A converse view predicts that agents which induce long-term depression (LTD) of synaptic efficacy in the amygdala may be useful in the amelioration of stress disorders and seziure. In the present study, I find that activation of group II metabotropic glutamate receptor (mGluR II) by (2S,3S,4S)-2-(carboxycyclopropyl) glycine (L-CCG) induces a LTD in the basolateral amygdala (BLA) neurons. The effect was concentration-dependent with a maximal inhibition of ~30%. The induction of L-CCG LTD required concurrent synaptic activity, presynaptic but not postsynaptic Ca++ increases and was independent of NMDA receptors. L-CCG LTD was associated with an increase in the ratio of paired-pulse facilitation (PPF) and was not occluded by low-frequency stimulation (LFS)-induced LTD suggesting that these two forms of LTD did not share a common underlying mechanism. After eliciting LTD with L-CCG, application of isoproterenol (Iso) increased the synaptic responses back to its original baseline demonstrating that chemically depressed synapses could be potentiated by another chemical. A selective PKA inhibitor KT 5720 by its own caused a depression of synaptic transmission and blocked L-CCG LTD, presumably by mimicking and thereby occluding any further depression. Taken together, these results suggest that L-CCG LTD is induced by presynaptically mGluR II-mediated inhibition of Ca++-sensitive adenylyl cyclase, resulting in a decrease in cAMP formation and PKA activation which leads to a long-lasting decrease in transmitter release. In conclusion, this study is the first demonstration of enduring synaptic depression induced by L-CCG in the naive amygdala slices. This finding may be of clinical significance in view of the facts that both kindling and fear conditioning resulted in a sustained enhancement of excitatory synaptic transmission in the amygdala, and patients with complex partial seizures of temporal lobe origin may experience behavioral disorders, such as depressive and anxiety-related symptoms. In the present, this study is the first demonstration of enduring synaptic depression induced by L-CCG in the amygdala slices. This finding may be of clinical significance in view of the facts that both kindling and fear conditioning resulted in a sustained enhancement of excitatory synaptic transmission in the amygdala, and patients with complex partial seizures of temporal lobe origin may experience behavioral disorders, such as depressive and anxiety-related symptoms. The second subject aims to study the Ca++ signalling on synaptic transmission in rat amygdala neurons. I found that release of Ca++ from the intracellular Ca++ store is necessary for LFS LTD. In addition, application of depolarizing pulses to BLA neurons induced LTD. Take together, these results imply that both Ca++ influx through voltage-dependent Ca++ channel and Ca++ release from intracellular stores are critically involved in LTD induction. In kindled rats, BAPTA-AM caused a less effect on the synaptic transmission compared with control animals, suggesting calcium-dependent processes downstream of Ca++ entry may change following Kindling. The third subject aims to study LFS LTD and L-CCG LTD in endocytosis. Application of N-ethylmalimide (NEM), which is know to inhibit N-etylmaleimide-sensitive fusion protein (NSF) function, can pevents LFS LTD but not L-CCG LTD, suggesting endocytosis engages the same mechanism as LFS LTD. In view of the results, L-CCG LTD and LFS LTD, underlie differential cellular mechanisms.