BDNF-Endocannabinoid Interactions in the Cerebral Cortex

描述(申请人提供)：这个项目的目标是探索以前未知的脑源性神经营养因子(BDNF)和大脑皮层内大麻系统之间的相互作用。BDNF和内源性大麻素在感觉、运动和联合皮质都有高表达，TrkB神经营养因子受体和1型大麻(CB1)受体在皮质各层的表达有显著重叠，其中以皮质2/3和5层的表达水平最高。这些神经调节系统中的任何一种都与一些神经和精神疾病有关，包括焦虑、抑郁、精神分裂症和癫痫，这两个系统目前都是开发新疗法的主要靶点。我们发现，BDNF对皮层抑制性突触的作用是通过BDNF诱导作用于突触前CB1受体的内源性大麻素的动员来实现的。这些研究将利用电生理学、分子生物学和药理学的方法探索BDNF诱导的抑制性突触合成和释放内源性大麻素的信号机制。拟议的研究还将扩展这些发现，以检查BDNF-大麻素在兴奋性突触上的相互作用，并探索这些相互作用在调节活性依赖的突触可塑性方面的功能相关性。从这些研究中获得的知识将为BDNF和内源性大麻素信号的调节和相互依赖提供深入的见解。关于这些神经调节剂之间相互作用的新的机械性见解可能为神经学和精神病学疾病的新治疗方法提供基础。

DESCRIPTION (provided by applicant): The goal of this project is to explore previously-unknown interactions between brain-derived neurotrophic factor (BDNF) and the endocannabinoid system in the cerebral cortex. Both BDNF and endocannabinoids are highly expressed throughout the sensory, motor, and association cortices, and there is a striking overlap of expression of trkB neurotrophin receptors and type 1 cannabinoid (CB1) receptors across cortical layers, with highest levels of expression in cortical layers 2/3 and 5. Disruption f either of these neuromodulatory systems has been implicated in several neurologic and psychiatric diseases, including anxiety, depression, schizophrenia, and seizure disorders, and both systems are currently major targets for the development of novel therapeutics. We found that the effects of BDNF at inhibitory cortical synapses are mediated by the BDNF-induced mobilization of endocannabinoids acting at presynaptic CB1 receptors. The proposed studies will explore the signaling mechanisms underlying BDNF-evoked synthesis and release of endocannabinoids at inhibitory synapses using electrophysiological, molecular biological, and pharmacological approaches. The proposed studies will also extend these findings to examine BDNF-cannabinoid interactions at excitatory synapses, and explore the functional relevance of these interactions in regulating activity-dependent synaptic plasticity. Knowledge gained from these studies will provide insights into the regulation and interdependence of BDNF and endocannabinoid signaling. New mechanistic insights regarding the interaction between these neuromodulators could provide the basis for novel therapeutic approaches to neurologic and psychiatric disease.