Regulation of synaptic plasticity by eCBs in adult and aged mammalian cortex

描述（由申请人提供）：与视觉功能相关的视觉功能退化包括空间敏锐度降低和刺激选择性丧失，这可能损害视觉-运动协调。有趣的是，GABA激动剂直接应用于老化的视觉皮层诱导刺激选择性的立即增加，这表明刺激选择性的下降可能是由于GABA能抑制的减少。在整个发育过程中，GABA能抑制增加，这可能会增加刺激选择性，降低成年人的眼优势可塑性。视觉皮层中可用的突触可塑性水平的灵敏测定是在双眼神经元中观察到的对单眼剥夺（MD）作出反应的眼优势移位。在青少年中，突触可塑性高，MD引起双眼神经元的眼优势的转变。虽然成年人的眼优势可塑性较低，但通过减少皮质抑制的操作可以提高眼优势可塑性。老年人视皮层的眼优势可塑性水平尚不清楚。视觉剥夺可以增强成人视觉系统中突触的可塑性，部分是通过调节GABA能抑制。无论是视觉剥夺还是药理学阻断抑制都不适用于人类群体。拟议的实验操纵皮质抑制间接通过使用1型大麻素受体（CBIRs）在成年出生后第150天（P150）和老年（P700）大鼠。CBIR定位于表达胆囊收缩素（CCK）的篮状细胞（一类GABA能中间神经元）的突触前末梢。CB 1 Rs的激活降低反馈抑制并促进突触能传递。我的初步数据表明，CB 1 R拮抗剂重新激活成人快速眼优势可塑性。MD后，从双眼视觉皮层收集的视觉诱发电位（VEP）显示，CB 1 R拮抗剂治疗的成年人对侧偏倚减少。本实验旨在探讨CB 1 R信号在成年和老年视觉系统中的眼优势可塑性、视觉功能和形态突触可塑性的作用。将使用硬膜下VEP、单单位记录以及树突棘分析来识别成年（PI 50）和老年（P700）大鼠中CB 1 R拮抗剂诱导的眼优势可塑性以及形态可塑性的层状位点。CB 1 R通路的操作可以增强成人的眼优势可塑性，为慢性MD后的功能恢复提供机会。在老年人群中，CB 1 R通路的操作可以恢复空间敏锐度和刺激选择性，从而改善老年视皮层的视觉功能。

DESCRIPTION (provided by applicant): Age-related degradation of visual functions includes decreased spatial acuity and a loss of stimulus selectivity, which can impair visuo-motor coordination. Interestingly, application of GABA agonists directly to the aged visual cortex induces an immediate increase in stimulus selectivity, suggesting the decline in stimulus selectivity may be due to a decrease in GABAergic inhibition. Throughout development GABAergic inhibition increases, which may increase stimulus selectivity and decrease ocular dominance plasticity in adults. A sensitive assay for the level of synaptic plasticity available in the visual cortex is the ocular dominance shift observed in binocular neurons in response to monocular deprivation (MD). In juveniles, synaptic plasticity is high and MD induces a shift in the ocular dominance of binocular neurons. Although ocular dominance plasticity is low in adults, it may be heightened by manipulations that reduce cortical inhibition. The level of ocular dominance plasticity in the aged visual cortex is unknown. Visual deprivation can enhance synaptic plasticity in the adult visual system, in part by regulation of GABAergic inhibition. Neither visual deprivation nor pharmacological blockade of inhibition is practical to translate to a human population. The proposed experiments manipulate cortical inhibition indirectly through use of type 1 cannabinoid receptors (CBIRs) in adult postnatal day 150 (P150) and aged (P700) rats. CBIRs are localized to presynaptic terminals of cholecystokinin-(CCK) expressing basket cells, a class of GABAergic interneurons. Activation of CB1 Rs decreases feedback inhibition and facilitates glutamatergic transmission. My preliminary data demonstrate CB1R antagonists reactivate rapid ocular dominance plasticity in adults. Following MD, visually evoked potentials (VEPs) collected from the binocular visual cortex reveal a decrease in the contralateral bias in adults treated with the CB1R antagonist. The proposed experiments explore CB1R signaling in ocular dominance plasticity, visual functions and morphological synaptic plasticity in the adult and aged visual system. Subdural VEPs, single-unit recordings as well as dendritic spine analyses will be used to identify the laminar locus of ocular dominance plasticity as well as morphological plasticity induced by CB1R antagonists in adult (PI 50) and aged (P700) rats. Manipulations of the CB1R pathway may enhance ocular dominance plasticity in adults, providing an opportunity for recovery of function following chronic MD. In the aged population, manipulations of the CB1R pathway may restore spatial acuity and stimulus selectivity and therefore improve visual function of the aged visual cortex.