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

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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.