【摘 要】
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Glycogen synthase kinase-3β(GSK-3β)is a key regulator of many cellular signaling pathways.In the dopamine(DA)system,GSK-3β is particularly involved in D2 receptor(D2R)-mediated signaling.We and others
【机 构】
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Department of Neurobiology & Anatomy,Drexel University College of Medicine,Philadelphia,PA 19129
【出 处】
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第九届海内外华人神经科学家研讨会(The 9th Symposium for Chinese Neuroscientis
论文部分内容阅读
Glycogen synthase kinase-3β(GSK-3β)is a key regulator of many cellular signaling pathways.In the dopamine(DA)system,GSK-3β is particularly involved in D2 receptor(D2R)-mediated signaling.We and others have shown that GSK-3β is required for D2R modulation synaptic transmission in the prefrontal cortex(PFC),a brain region that is critical for cognitive function.Increasing evidence indicates that D1 receptor(D1R)and D2R are respectively restricted to a subpopulation of neurons not only in the striatum,hippocampus,but also in the PFC.However,it is still unclear whether GSK-3β exhibits distinct cell-specific roles in prefrontal function.In the present study,we examined the cortical role of GSK-3β in a novel mouse model,either conditional genetic ablation of GSK-3β in D2-neurons(D2R-GSK-3β-/-mice)or D1-neurons(D1R-GSK-3β-/-mice)with their litter mate controls.In PFC layer V pyramidal neurons,we found that neuronal excitability was increased in both D1RGSK-3β-/-and D2RGSK-3β-/-mice,with spike number increasing even more significantly in D1RGSK-3β-/-vs.D2RGSK-3β-/-mice.Furthermore,both NMDA receptor(NMDAR)-mediated currents and protein levels of NMDAR subunits in the PFC were significantly enhanced without effects on AMPA receptor(AMPAR)-EPSCs and protein expression in D2RGSK-3β-/-mice.Interestingly,both AMPAR-mediated currents and GluR1 protein levels were elevated but NMDAR function and expression were unaffected in D1RGSK-3β-/-mice,indicating a cell type-specific regulation of glutamate receptors by GSK-3β.In addition,DA sensitivities in modulation of NMDAR shifted in different directions in D2R3β-/-mice and D1RGSK-3β-/-mice.Accompanied with the change of NMDAR,the spine number was also increased in layer V of PFC neurons in D2RGSK-3β-/-mice but not in D1RGSK-3β-/-mice.Consistently,cortical LTP was enhanced while LTD was attenuated in D2RGSK-3β-/-mice.Together,these data suggest that GSK-3β plays a cell-type-specific action on neuronal and synaptic function in the PFC.
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