Analysis of visual cortical function and circuits in a mouse model of Rett- Syndrome

Rett Syndrome (RTT), a neurodevelopmental disorder, is caused by de novo mutation of MECP2 gene on X- chromosome and it is characterized by regression during the first few years of life. Specifically in the mouse visual cortex, evidence has shown that lack of Mecp2 disrupts development of inhibitory interneuron systems, leading to compromised balance of inhibitory and excitatory cortical neuronal function. In my thesis, I worked on Mecp2-heterozygous females, which are considered a closer model of the human condition. I performed visual evoked potential (VEP) in adult Mecp2 Het that exhibited either mild or severe RTT-like symptoms, according to the 12-point RTT phenotypic score (Guy et al., 2001). Mecp2 Het mice displayed a significant decrease in the amplitude of VEP response in comparison with their wild-type (WT) littermates. Interestingly, such defect was already present in Mecp2 Het mice with mild symptomatology and worsened with the disorder progression. Moreover, VEP response to high spatial frequencies was lost, resulting in a shift down in the spatial frequency (SF) tuning curve and significantly lower spatial resolution. I then tested whether administration of low dosage of NMDAR antagonist, ketamine (8mg/kg, ip) for six weeks (two weeks on/two weeks off) was sufficient to ameliorate the visual function in Mecp2 Het mice. I found an increase in the VEP amplitude in comparison with the Het treated with vehicle. In addition, we observed this increase in the response to all stimuli resulting in an amelioration of the visual acuity. Finally I characterized the inhibitory/excitatory imbalance in visual cortex using immunohistochemistry., finding an increase in the thalamic excitatory markers that precedes the full onset of the regression. Together our results indicate that visual processing is impaired across Mecp2 mouse models and provide further evidence that targeting NMDAR function is a feasible and an effective therapeutic treatment for Rett Syndrome.