Cannabinoid Modulation of Cortical Synaptic Transmission

描述（由申请人提供）：大脑皮层涉及各种各样的功能，从感觉处理和运动协调到感知、语言生成和其他高级认知能力。这些不同的过程依赖于锥体细胞的功能，锥体细胞负责皮层区域之间的连接以及与皮层下结构的连接。反过来，锥体细胞的活动受到不同类别的GABA能抑制性中间神经元的严格控制，这些抑制性中间神经元支配锥体细胞上功能分离的结构域，以调节动作电位计时、兴奋性输入的功效和同步活动。这些中间神经元在体内以高速率放电，并对锥体细胞提供有效的抑制，因此这种抑制性音调的调节对于适当的皮质功能是必不可少的。最近的解剖学和生理学数据表明，大麻素系统在调节新皮层中的GABA能中间神经元中起重要作用。1型大麻素（CB 1）受体是前脑中最高表达的G蛋白偶联受体之一，并介导外源性大麻素对认知、感觉和运动过程的影响。内源性大麻素配体以高度的空间和时间特异性从锥体神经元合成和释放，并且至少部分地通过与中间神经元的突触前末端上的受体结合来调节GABA释放而起作用。内源性系统的特异性表明，外源性大麻素对认知过程的破坏性影响可能是由于该系统的非选择性全局激活。本研究的长期目标是了解内源性大麻素信号在调节新皮质功能中的生理意义。拟议研究的具体目标是：1）确定内源性大麻素对皮质突触抑制的影响，2）测试大麻素选择性调节锥体细胞抑制性传入的特定功能类别的假设，以及3）研究大麻素信号传导对锥体细胞活性的影响。

DESCRIPTION (provided by applicant): The cerebral cortex is involved in a huge diversity of function, ranging from sensory processing and motor coordination to perception, generation of language, aM other higher-order cognitive abilities. These varied processes rely on the function of pyramidal cells, which are responsible for connections between cortical areas as well as connections to subcortical structures. Pyramidal cell activity, in turn, is tightly controlled by distinct classes of GABAergic inhibitory interneurons, which innervate functionally segregated domains on pyramidal cells to regulate action potential timing, the efficacy of excitatory inputs, and synchronous activity. These interneurons fire at high rates in vivo and provide potent inhibition to pyramidal cells, thus regulation of this inhibitory tone is essential for proper cortical function. Recent anatomical and physiological data indicate that the cannabinoid system plays an important role in modulating GABAergic interneurons in the neocortex. The type 1 cannabinoid (CB 1) receptor is one of the most highly expressed G-protein coupled receptors in the forebrain, and mediates the effects of exogenous cannabinoids on cognitive, sensory, and motor processes. Endogenous cannabinoid ligands are synthesized and released from pyramidal neurons with a high degree of spatial and temporal specificity, and act at least in part by binding to receptors on the presynaptic terminals of interneurons to regulate GABA release. The specificity of the endogenous system suggests that the disruptive effects of exogenous cannabinoids on cognitive processes may result from the non-selective global activation of this system. The long-term objective of this research is to understand the physiological significance of endogenous cannabinoid signaling in the regulation of neocortical function. The specific goals of the proposed studies are to: 1) determine the impact of endogenous cannabinoids on cortical synaptic inhibition, 2) test the hypothesis that cannabinoids selectively modulate a particular functional class of inhibitory afferents to pyramidal cells, and 3) investigate the consequences of cannabinoid signaling for pyramidal cell activity.