发育关键期双酚A暴露对神经突触功能的影响及机理研究

Bisphenol A, a kind of endocrine disrupter, always causes side-effect on human several system due to its extensivly enviornmental exposure. Recently, lots of studies showed that Bisphenol A exposure could induce the hyperactivity and decrease of memory ability on the juvenile rodents, but its physiological change and underlying mechanism are almost unknown. The present study will explore whether developmental Bisphenol A exposure induces synaptic alteration and clarify its underlying mechanisms by patch-clamp technology,two-photo micrscopic imaging and morphological staining methods. Firstly, the change of electrophysiological properties, especially,the excitatory and inhibitory synaptic transmission will be detected after low dose Bisphenol A exposure by patch-clamp recording. It will provide physiologcial evidence to explain the Bisphenol-A related behavior change. Secondly,the morphological alteration of neurons will be examined by two-photon and laser confocal microscopic imaging technology in real-time observation and thus explain the structural basis of the physiological functions change.It also could disovle the debate on the alteration of spine density after Bisphenol-A exposure. Thirdly, the alteration expression or activity of proteins, which could regulate the remodeling of synaptic structure, will be examined by molecular methods to explain the mechanisms of synaptic transmission alteration after Bisphenol A exposure. In conclusion, the present study will explore the Bisphenol A induced synaptic alteration and its underlying mechanisms. It will show light on the diagnosis and therapy on the central nervous system damage after Bisphenol A exposure.

在日常生活中广泛使用的化工原料双酚A是一种内分泌扰乱剂，会引起多种疾病发病率的增高。近年来研究发现，双酚A暴露导致幼年大鼠学习记忆能力的下降和多动症的发生，但对于内在生理变化基础以及分子机理知之甚少。本项目拟以发育关键期大鼠和离体海马神经元为实验对象，采用膜片钳记录、双光子显微成像等实验方法，从以下几个方面较为系统地研究双酚A导致中枢神经系统损伤的机制：1、研究双酚A对海马神经元电生理反应特性的影响，特别是对兴奋性和抑制性突触传递的影响，探索造成这些变化的可能机制，为相关行为特征改变提供生理学证据；2、研究不同时程双酚A暴露对树突形态的影响，验证电生理特性变化的结构基础；3、利用分子生物学手段，探索双酚A引起树突形态改变的可能分子途径。本研究将为双酚A安全剂量标准的制定提供参考依据，也为临床分析和防治双酚A对儿童中枢系统的影响提供重要的生理基础和实验依据。

在日常生活中广泛使用的化工原料双酚A是一种内分泌扰乱剂，近年来研究发现，双酚A暴露导致幼年大鼠学习记忆能力的下降和多动症的发生,但对于内在生理变化基础以及分子机理知之甚少。本项目采用膜片钳记录、双光子显微成像、多通道电生理记录等实验方法，从以下三个方面较为系统地阐述了双酚A导致中枢神经系统损伤的机制：1、发育期双酚A暴露引起成年期海马相关的空间记忆损伤，并且伴随着树突棘密度的降低，我们通过海马神经元体外培养，进一步发现这些功能和结构的损伤主要由于WNT分子通路活性的降低所介导；2、幼年期双酚A暴露引起的前额叶相关的物体识别能力下降，并且伴随着焦虑样行为发生，同时树突棘密度也有明显降低，而调控发育及代谢的mTOR通路在其中发挥了重要作用；另外，海马区相关的空间学习记忆能力的下降，伴随着长时程突触增益的降低，我们还发现这些生理和行为上的损伤是由兴奋性突触前的递质释放和突触后受体的功能损伤共同作用的结果；3、在“更高分辨率”的初级视皮层的单个神经元上，静脉急性双酚A暴露导致视觉相关的生理功能（方位调谐）明显受损，其中单细胞的信噪比和神经元活性的降低可能起到至关重要的作用。本研究将为双酚A安全剂量标准的制定提供参考依据，也为临床分析和防治双酚A对儿童中枢系统的影响提供了重要的生理基础和实验依据。