Cell-type specific contributions to Rett Syndrome : neuronal and astrocytic signaling and sensory processing

Abstract

Loss of function mutations in the X-linked gene encoding for MeCP2 are the underlying genetic cause for Rett Syndrome (RTT), a devastating neurodevelopmental disorder that primarily affects girls. While the function of this transcriptional regulator remains elusive and complex, recent focus has turned to downstream signaling pathways as putative targets for novel therapeutics. The complexity of MeCP2 function is compounded by the heterogeneity of cell types in the brain, with recent evidence implicating glia cells in RTT pathophysiology. The focus of my thesis has been two-fold: exploring signaling mechanisms downstream of MeCP2 and the potential of IGF-1 as a therapeutic for RTT, and examining functional astrocyte sensory processing in healthy and impaired circuits. I present evidence that IGF-1 levels are reduced in mouse models of RTT and systemic treatment with IGF-1 leads to improvements in lifespan, respiratory patterns, and social behaviors. These effects are accompanied by increased synaptic proteins, activation of signaling pathways, and enhanced excitatory transmission, as well as effects on plasticity in visual cortex circuits. Astrocytes, known to contribute to synapse formation and maintenance, have been implicated alongside neurons as contributors to the RTT phenotype. They express the two most abundant glutamate transporters in the brain responsible for the majority of glutamate clearance from synapses. Indeed, lack of MeCP2 in astrocytes leads to a reduction in signaling pathways and aberrant glutamate transporter expression, with strong implications for synaptic and circuit activity. Efficient processing of visual information requires processing salient features while overcoming the inherent variability in neuronal networks. Natural movies evoke reliable responses from pyramidal neurons in visual cortex and my work reveals that discrete microdomain regions of visual cortex astrocytes also exhibit temporally reliable and spatially correlated responses to natural scenes. I show that glutamate transporters, which influence astrocytic Ca 2 signaling and synaptic transmission, regulate the reliability of astrocyte microdomain responses and thus contribute crucially to visual information processing. Finally, I show that in a RTT mouse model, astrocyte microdomains elicited by visual stimuli are reduced in size, consistent with the reduced synaptic transmission and neuronal responses observed in these mice.