Cannabinoid Modulation of Cortical Synaptic Transmission

描述(申请人提供)：大脑皮层参与多种功能，从感觉处理和运动协调到感知、语言生成和其他更高级的认知能力。这些不同的过程依赖于锥体细胞的功能，锥体细胞负责皮质区域之间的连接以及与皮质下结构的连接。反过来，锥体细胞的活动又受到不同类别的GABA能抑制中间神经元的严格控制，这些神经元支配锥体细胞上功能分离的区域，以调节动作电位的时序、兴奋性输入的有效性和同步活动。这些中间神经元在体内以高速率激发，并对锥体细胞提供有效的抑制，因此调节这种抑制音调对于正常的皮质功能至关重要。最近的解剖学和生理学数据表明，大麻素系统在调节大脑皮层GABA能中间神经元方面起着重要作用。Cb1受体是前脑中表达最高的G蛋白偶联受体之一，介导外源性大麻素对认知、感觉和运动过程的影响。内源性大麻素配体是从锥体神经元合成和释放的具有高度时空特异性的配体，至少部分通过与中间神经元突触前末端的受体结合来调节GABA的释放。内源性系统的特殊性表明，外源性大麻素对认知过程的干扰作用可能是由于该系统的非选择性全局激活所致。本研究的长期目标是了解内源性大麻素信号在新皮质功能调节中的生理学意义。这些研究的具体目标是：1)确定内源性大麻素对皮质突触抑制的影响，2)检验大麻素选择性调节锥体细胞特定功能类抑制性传入的假设，3)研究大麻素信号对锥体细胞活动的影响。

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.