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

描述（由申请人提供）：与年龄相关的视觉功能退化包括空间灵敏度下降和刺激选择性丧失，这可能损害视觉运动协调。有趣的是，将GABA激动剂直接应用于衰老的视觉皮层会导致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，可能增加刺激选择性，降低成人的眼优势可塑性。在单眼剥夺（MD）下观察到的双眼神经元的眼优势转移是一种检测视觉皮层突触可塑性水平的灵敏方法。在幼体中，突触可塑性很高，MD诱导双眼神经元的眼优势转移。虽然成人的眼优势可塑性较低，但可以通过减少皮质抑制的操作来增强。老年视觉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的突触可塑性，部分是通过调节gaba能抑制。无论是视觉剥夺还是抑制的药理学封锁都不能转化为人类群体。提出的实验通过使用1型大麻素受体（CBIRs）间接操纵皮层抑制在成年大鼠出生后150天（P150）和老年（P700）。CBIRs定位于表达胆囊收缩素-(CCK)的篮细胞（一类gaba能中间神经元）的突触前末端。CB1 Rs的激活减少反馈抑制，促进谷氨酸能传递。我的初步数据表明，CB1R拮抗剂可以在成人中重新激活快速的眼优势可塑性。MD后，从双眼视觉皮层收集的视觉诱发电位（vep）显示，接受CB1R拮抗剂治疗的成年人对侧偏视减少。本实验旨在探讨CB1R信号在成人和老年视觉系统的眼优势可塑性、视觉功能和形态突触可塑性中的作用。硬膜下vep、单单元记录以及树突棘分析将用于鉴定CB1R拮抗剂在成年（PI 50）和老年（P700）大鼠中引起的眼优势可塑性和形态可塑性的层流位点。操作CB1R通路可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。在老年人中，操作CB1R通路可恢复空间灵敏度和刺激选择性，从而改善老年人视觉皮质的视觉功能。

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.