Characterisation of anatomical and functional deficits in a mouse model of Rett Syndrome

Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X-linked gene, MECP2, has a clinical phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype and Mecp2 knock-out animal models provide an excellent platform for investigating the role of MeCP2 in the brain development. In this thesis, I used the Mecp2-stop mouse model to address the effects of MeCP2 deficiency in the central nervous system. First, I assessed the genotype-phenotype relationship at the level of the whole organism by detailed temporal mapping of the RTT-like neurological signs. I also addressed the genotype-phenotype relationship at the level of neuronal networks by assessing alterations in neuronal (cortical) density including potential alterations across morphologically discrete cell subtypes. Finally, I also investigated the genotype-phenotype relationship at the level of the synapse by assessing RTT-related changed in synaptic plasticity. Whole organism phenotyping using observational scoring revealed the male hemizygous Mecp2-mutant mice (Mecp2stop/y) to show an early (from ~5 weeks) and aggressive onset of signs including locomotor and other general features. Correlated studies at the level of the synapse revealed the severity of gross organismal pathology to mirror a progressive decline in both short- and long-term forms of synaptic plasticity as measured in the CA1 region of the hippocampus. Specifically, extracellular field recordings in acute hippocampal slices from strongly symptomatic Mecp2-stop mice showed long-term plasticity (LTP) at the Schaffer-collateral-to-CA1 pyramidal synapse to be 40.2 ± 1.6 % of age-matched wild-type littermate controls. In addition, putative presynaptic short-term forms of plasticity (post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF)) were also decreased in the Mecp2-stop hippocampus (45 ± 18.8 % and 78 ± 0.1 % of wild type for PTP and PPF respectively; all p