阿尔兹海默、帕金森和精神分裂症等脑疾病，都伴随钙离子/ 钙调蛋白依赖性蛋白激酶II （calcium/calmodulin dependent protein kinase II，CaMKII） 活性异常和灵活性学习受损。齿状回脑区（dentate gyrus，DG）在灵活性学习中起重要作用，CaMKII异常也会导致DG功能异常，但机制尚未探明。我们发现上调DG区βCaMKII（CaMKII亚型之一）表达，损害DG灵活性学习和DG长时程抑制（Long-term depression,LTD)。在此数据基础上，本项目将采用βCaMKII-F90G转基因小鼠，区域和分子特异地、可逆地、实时上调DG区βCaMKII表达，通过行为学、形态学、电生理学和分子生物学技术，进一步探明上调DG区βCaMKII表达，损害灵活性学习和DG区LTD的机制，有望为灵活性学习障碍的脑疾病研究提供新启示。

A variety of neurological diseases, such as Alzheimer's disease, Parkinson's disease and schizophrenia are accompanied by abnormal activity of calcium/calmodulin-dependent protein kinase II (CaMKII) and by impaired cognitive flexibility. Many studies have suggested that dentate gyrus (DG) plays an important role in cognitive flexibility, and dysregulation of CaMKII activity can cause dysfunction of DG. However, it is unclear how CaMKII plays the role in cognitive flexibility. We have found that up-regulation of βCaMKII （an isoform of CaMKII）expression in DG impaired DG-related cognitive flexibility and long-term depression of DG (DG-LTD). Based on our above data, in the present study, combining behavioral, morphological, in vitro electrophysiological with molecular biological techniques, we will use the βCaMKII-F90G transgenic mice, in which level of exogenous βCaMKII expression in dentate gyrus can be manipulated on the scale of minutes reversibly during memory process, to investigate how up-regulation of βCaMKII expression impairs cognitive flexibility and DG-LTD . This study has an important implications for elucidating the pathomechanism of neurological diseases with cognitive flexibility disorders.