Neuromodulatory and metaplastic regulation of long-term synaptic plasticity in the primary visual cortex of adult rats.

Abstract

Synaptic plasticity in the neocortex of mammals is influenced by various neuromodulators and metaplasticity mechanisms. These regulatory processes allow synaptic networks to operate and adjust to various behavioral states and the constantly changing inputs from the sensory environment. The neurochemical milieu created by neuromodulators is an important regulator of synaptic plasticity at the time of induction, while metaplastic-processes regulate neuronal networks based on their history of activity. This thesis investigated the effects of the neurochemical milieu and past experiences (learning) on long-term potentiation (LTP) of synapses in vivo in the primary visual cortex (V1) of adult rats. Initial experiments revealed that the application of the neuromodulator serotonin (5-HT) in V1 was ineffective at altering LTP. However, LTP was facilitated in the presence of a 5-HT1A-receptor antagonist. Interestingly, in juvenile rats, the same antagonist exerted the opposite effect (i.e., inhibited LTP), indicating an age-specific role of 5-HT1A receptors in the gating of V1 synaptic plasticity. Next we examined the role of visual experience (visual discrimination training) on LTP in the adult V1. Rats trained to discriminate visual cues in a Y-shaped water maze apparatus subsequently exhibited enhanced LTP compared to naive or control (visually untrained) rats. The facilitation of LTP in visually trained rats was reversed by an antagonist of GluN2B subunits of the N-methyl-D-aspartate receptor (NMDAR) in V1. Consequently, we examined potential changes in NMDAR functioning in rats trained in the visual discrimination task. Patch clamp recordings of principal neurons in V1 revealed that behavioral training enhanced GluN2B-mediated NMDAR conductance. Finally, we examined the behavioral consequences of blocking GluN2B receptors during visual discrimination training, using a sequential task that involved two distinct rounds of training (involving different sets of visual cues). Results of these experiments showed that systemic GluN2B antagonism during the second round of visual training impaired task acquisition relative to controls. Together, the experiments in this thesis highlight the importance of neuromodulation and metaplasticity in V1 for the gating of LTP, one of the principal mechanisms of learning and memory storage in the cortex of mammalian species.