|dc.description.abstracteng||PSD-95 belongs to the family of DLG-MAGUKs (Discs-large membrane-associated guanylate kinases), and it plays an important role in organizing postsynaptic signaling and synaptic transmission in excitatory synapses. The expression level of PSD-95 can control the basal AMPA receptor-mediated synaptic transmission. It has also been suggested that PSD-95 plays a crucial role in excitatory synapse maturation and its expression level directly correlates to the number of silent synapses. Additionally, PSD-95 is involved in long-term synaptic plasticity. Knock-out (KO) of PSD-95 facilitates LTP induction and prevents LTD. In visual cortex, which is a common experimental model to study cortical developmental plasticity, the number of silent synapses decreases during the development. Also, the long-term synaptic plasticity is shown to be important in cortical developmental plasticity. Therefore, it is interesting to analyze the role of PSD-95 in synaptic maturation and plasticity in the visual cortex. I performed electrophysiological analysis from acute slices of the PSD-95 KO mice at different developmental stages. In PSD-95 KO mice the AMPAR/NMDAR EPSC ratio was consistently lower and the number of AMPAR silent synapses was higher compared to wild-type littermates. Unlike control mice, where the silent synapse number decreased during development, the number of silent synapses in PSD-95 KO mice retained at a high level. This result is consistent with the observation of juvenile ocular dominance plasticity (ODP) in adult KO mice. This high plasticity level was not mediated by reduced inhibition or enhanced LTD, the two major mechanisms generally considered to be involved in ODP. So the high number of silent synapse may serve as a substrate for this plasticity. On the other hand, this heightened plasticity also resulted in an unstable neuronal network in the visual cortex that can not be consolidated during the development, causing an impairment in orientation discrimination in KO animals.
Furthermore, to understand this PSD-95 dependent AMPAR regulation and synaptic maturation, I need more detailed analysis of the underlying mechanism. The fact that overexpression of PSD-95α can enhance the AMPAR function through unsilencing the silent synapses, while PSD-93α does not express this ability, provided me the chance to perform the structure function analysis between them. I identified one amino acid in the N-terminus that played an important role in the enhancement effect of AMPAR function. This amino acid is part of the phosphopeptide that activates the Src family kinase, hence this includes Src kinase in the pathway responsible for AMPAR regulation by PSD-95.||de