Mechanisms of ocular dominance plasticity in the juvenile and adult mouse visual cortex

Abstract

Ocular dominance (OD) plasticity is a classic example of bidirectional experience-dependent plasticity in the primary visual cortex. This form of plasticity is most robust during early postnatal development (termed the "critical period"), when monocular deprivation (MD) leads to a rapid weakening of responses evoked through the deprived eye followed by a delayed strengthening of non-deprived eye inputs. It has been proposed that these bidirectional changes occur as a three-stage process: first, degradation of patterned visual input weakens deprived-eye responses via homosynaptic long-term depression (LTD); this is accompanied by a shift in the plasticity modification threshold (0m) that determines the direction of synaptic plasticity, such that synaptic strengthening is favored over synaptic weakening; finally, weak open-eye responses are strengthened via the mechanisms of homosynaptic long-term potentiation (LTP). Despite the growing evidence supporting this model of experience-dependent synaptic modification, the exact molecular and synaptic mechanisms that are responsible for these processes remain controversial. In my thesis work, I address three questions. First, I attempt to parse the relative contribution of excitatory and inhibitory processes to expression of the OD shift in order to understand how deprived-eye depression is expressed in the cortex. To address this, I first induce a shift in OD with 3 days of MD and then use several pharmacological methods to shut off cortical inhibitory synaptic transmission. I demonstrate that rapid deprived-eye depression is strongly expressed at excitatory thalamocortical synapses without any influences of polysynaptic intracortical inhibition. In the second part of my work, I try to resolve the nature/identity of the molecular mechanism that underlies the regulation of [theta]m. Using a transgenic mouse model, I find that a reduction in the NR2A/B subunit ratio of the N-methyl-d-aspartate (NMDA) receptor during MD alters the qualities of OD plasticity by impairing weakening of deprived-eye inputs and enhancing strengthening of open-eye inputs. These findings suggest that NMDAR subunit composition may specify the value and the rate of adjustment of synaptic 0m, which in turn determines the bidirectional cortical response to MD. The final portion of my thesis addresses the factors that limit OD plasticity beyond the critical period. I test the hypothesis that the developmental increase in intracortical GABAergic inhibitory synaptic transmission is a fundamental restricting factor for adult cortical plasticity and demonstrate that parvalbumin-expressing fast-spiking basket cells are specifically implicated in the absence of juvenile-like deprived-eye depression in adult mice.