OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depre...OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.展开更多
文摘OBJECTIVE Major depressive disorder(MDD) is a common mental illness,which shows serious dysfunction in emotion,motivation and cognition. The imbalance of monoamine neurotransmitter is the classic pathogenesis of depression,but more and more evidence indicates that glutamatergic transmission may be the key factor leading to the occurrence of depression. However,the role of the membrane expression and regulation of glutamate receptors in the development of depression has not been elucidated. To address this issue,we have done series of experiments. METHODS Different methods and techniques,such as behavior,morphology,molecular biology and electrophysiology,were applied to investigate the impact of glutamate receptors and their subunits in the regulation of synaptic plasticity and the mechanism in depressive animal models. RESULTS Chronic social defeat stress(CSDS) can induce depressive behaviors in wildtype(WT) mice but not caspase-1 knockout(KO) mice. Further experiments showed that,in WT mice,CSDS induced a significant decrease in the membrane expression levels of the GluR1 and GluR2 subunits of AMPA receptors,the amplitudes of m EPSC in hippocampal CA1,meanwhile the long-term potentiation(LTP) at hippocampus SC-CA1 pathway was also impaired. Oppositely,this CSDS-induced reduction of the membrane expression of AMPA receptors was prevented by the knockout of caspase-1 or caspase-1 inhibitor,in which the expression of GluA1 and GluA2 were upregulated from(60.2±3.4)% and(63.9±3.7)% to(120.1±5.9)%and(112.6±9.6)%,respectively,while the total protein level of AMPA receptor subunits were not affected.On the other hand,a chronic intracerebroventricular injection of IL-1β,a downstream signal molecule of caspase-1,could induce depression-and anxiety-like behaviors in caspase-1 KO mice. CONCLUSION The caspase-1 can mediate the stress-induced depression-like behaviors by down-regulation of the membrane expression of AMPA receptors in hippocampus,the inhibition or knock-out of caspase-1can increase the expression of AMPA receptors in the membrane,thus reversing the depression-like behavior. Caspase-1 may serve as new target for depression therapy.
