NDRG2缺失致脑糖原代谢异常在注意缺陷多动障碍发病中的作用及机制

注意缺陷多动障碍（ADHD）严重影响患儿的学习和生活，但其发病机制不清。脑糖原主要存在于星形胶质细胞，可以为神经元快速供能。神经影像学研究表明ADHD患儿大脑皮层存在慢性能量供应不足，可能与脑糖原代谢障碍有关。本课题组前期研究发现：Ndrg2-/-小鼠表现ADHD样行为和增高的兴奋性神经传导，前额叶皮质出现糖原累积，并且糖原分解代谢关键酶PYGB蛋白表达水平显著降低。结合以往文献和我们的前期工作，提出如下假说：NDRG2缺失影响PYGB的表达和功能，导致星形胶质细胞糖原分解障碍，不能给神经元快速供能，前额叶皮质处于慢性能量缺乏状态，导致兴奋性突触发育异常，神经兴奋-抑制传导失衡，最终表现ADHD样行为。本课题拟从分子、细胞、组织、动物四个层次，运用细胞生物学、生物化学和神经生物学等方法阐明NDRG2缺失在脑糖原代谢异常和ADHD发病中的作用和机制，为ADHD的诊断和治疗提供新的策略。

Attention deficit/hyperactivity disorder (ADHD), a childhood-onset psychiatric disorder, may result in future academic failure and poor life quality. However, the underlying pathophysiology mechanism in ADHD still largely uncovered. Brain glycogen is found mainly in astrocytes, which can rapidly provide energy to neighboring neurons. Neuroimaging studies have shown that there were chronic energy supply deficit in the cerebral cortex of ADHD children, which may be associated with the brain glycogen metabolism disturbance. Our previous study found that Ndrg2-/- mice exhibited ADHD-like behaviors and increased excitatory transmission. We also found the increased glycogen and significantly decreased level of PYGB protein, a key glycogenolysis enzyme, in the prefrontal cortex of Ndrg2-/- mice. According to the previous studies and our preliminary results, we hypothesized that NDRG2 deficiency affect the expression and function of PYGB, which resulted in accumulated glycogen in astrocytes and blocked rapid energy supply for neighboring neurons. Therefore, there was chronic energy deficiency in the prefrontal cortex, which led to abnormal development in excitatory synapses, imbalanced excitatory/inhibitory transmission, and eventually ADHD-like behaviors. This project will carry out systematical research to confirm the above hypothesis from the levels of molecule, cell, tissue and animal. The aim of this project is to elucidate the role of NDRG2 deficiency in abnormal brain glycogen metabolism and ADHD developing by using cell biology, biochemistry and neurobiology methods, thus to provide new strategies for the diagnosis and treatment for ADHD.