Hippocampal Synaptic Plasticity in a Murine Knock-Out Model of Fragile X Syndrome

Abstract

The dissertation is divided into two separate experiments that explore the effects of visual-spatial learning on PSD-95 dorsal hippocampal expression. Specifically, the aim of these studies was to explore the effect of learning an assay, the Hebb-Williams mazes, on the protein expression of PSD-95 in Fmr1 KO mice. PSD-95 is an important scaffolding protein hypothesized to be involved in learning and memory. In cellular models of Fragile X Syndrome it has been shown to be dysregulated but it has never been measured following behavioural learning. Establishment of a deficit using an ecologically valid behavioural assay could lead to the development of novel interventions. Study one employed a subset of the Hebb-Williams mazes of various levels of difficulty to evaluate PSD-95 protein expression in Fmrp intact and Fmr1 KO mice following learning. The results revealed significant increases in PSD-95 protein expression in control runners when compared to Fmr1 KO mice. There was a negative correlation between PSD-95 protein levels and mean total errors on the mazes meaning that as expression was increased, errors were decreased. The goals of study two were to reverse the molecular and behavioural deficits using pharmacological antagonist treatment shown to be effective in cellular models of Fragile X Syndrome. Fmr1 KO mice were treated with either saline or 20 mg/kg of a metabotropic glutamate receptor antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP). Relative to saline treated controls, drug treated Fmr1 KO mice made fewer errors on the same subset of Hebb-Williams mazes used in study one. Latency to complete these mazes did not differ between groups, indicating that MPEP treatment does not adversely affect motor functioning. Protein assessment revealed that PSD-95 was selectively rescued in MPEP treated mice and not saline controls. Similar to study one, a negative correlation between PSD-95 protein levels and mean total errors was observed. When taken together, these studies indicate that protein deficits are associated with a deficit of learning that can be reversed with a selective glutamate receptor antagonist. One of the strengths of the Hebb-Williams mazes is that performance is measurable without floor or ceiling effects, which plague other common behavioural assays. These data further suggest that pharmacological antagonist treatments may be promising in correcting the learning deficits in human Fragile X Syndrome patients.