Methyl-CpG binding protein 2 (MeCP2) is a chromatin-associated protein which functions in epigenetic gene regulation. Mutations in MeCP2 lead to a variety of neurological disorders, including Rett Syndrome (RTT). Learning and memory deficits are prevalent in RTT, as are sleep disturbances: throughout the night, RTT patients spend less time in Stage 3 non-rapid eye movement (NREM) sleep. Delta oscillations (0.5 – 4 Hz) are the main constituent of Stage 3 NREM sleep, and are thought to be vital for sleep-related memory consolidation.
In this thesis, the mechanisms and networks involved in delta oscillation generation were studied in a mouse model of RTT. In isolated sections of somatosensory cortex, loss of MeCP2 function resulted in the disruption of pharmacologically-induced cortical delta oscillations. In contrast, delta oscillations that arise via the thalamic generator remained intact. Pre-symptomatic Mecp2-null animals showed partial preservation of cortical delta oscillations, suggesting that neurological deficits precede phenotype onset.
Intracellular current clamp recordings revealed that loss of MeCP2 function impairs the firing pattern of layer V intrinsically bursting pyramidal neurons, the cells responsible for generating the cortical delta rhythm. The bursting mechanism of these cells was restored by reducing the intracellular calcium ion concentration in these cells, which was also sufficient to reinstate the cortical delta rhythm.
Finally, delta oscillations, sleep spindles and hippocampal sharp-wave ripples were studied in vivo during NREM sleep, since the coupling of these rhythms is thought to facilitate sleep-related memory consolidation. Rhythm coupling was unaffected by the loss of MeCP2 function, however the incidence of all three rhythms was significantly reduced, resulting in impaired performance on a hippocampus-dependent spatial memory task.
The implication of these results on our understanding of the precise role of MeCP2 in coordinating NREM-associated brain rhythms and on the development of learning and memory deficits in RTT are discussed.
