No abstract

Rett syndrome is an autism-spectrum disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2). While subtle decreases in synaptic plasticity have been detected within cortical and hippocampal neurons of Mecp2-null mice, only minimal information exists regarding how the loss of MeCP2 affects network activity in the brain. To address this issue, we compared the intrinsic network activities of Mecp2-null hippocampal slices derived from symptomatic mice to wild-type slices. Extracellular and whole-cell patch recordings revealed that although spontaneous, IPSP-based rhythmic activity is present in Mecp2-null slices; its frequency is significantly reduced from wild-type. This reduction was not associated with alterations in the gross electrophysiological properties of hippocampal neurons, but was associated with a decreased level of spontaneous glutamate receptor-mediated synaptic currents in hippocampal CA3 neurons. Paradoxically, however, repetitive sharp wave-like discharges were readily induced in the Mecp2-null hippocampal slices by a brief train of high-frequency stimulation commonly used to establish long-term potentiation at wild-type slices. Taken together, our data indicate that the Mecp2-null hippocampal CA3 circuit has diminished basal inhibitory rhythmic activity, which in turn renders the circuitry prone to hyperexcitability.

Mutations in the MeCP2 gene cause Rett syndrome, a neurologic condition affecting primarily young girls. To gain insight into the normal function of MeCP2, we examined its temporal and spatial expression patterns, and immunoreactive prevalence, during late embryonic and perinatal brain development. MeCP2 mRNA was detected in most regions of the developing rat brain by the late embryonic stage. Regions displaying the strongest mRNA expression include the hippocampus, cortex, and cerebellum, and moderate expression was observed in most other brain regions. At the protein level, MeCP2 was strongly expressed in adult forebrain neurons, but was not detected in astrocytes. The nonubiquitous expression of MeCP2 was also observed in the embryonic cortex, as about one-third of acutely dissociated embryonic day 14 neuroepithelial cells failed to stain with MeCP2. To test whether MeCP2 expression correlates with neuronal differentiation, colocalization of MeCP2 expression with either the precursor cell marker nestin or the young neuronal marker beta-III tubulin was examined in the same acutely dissociated cortical cells. Although strong MeCP2 expression was detected in approximately 75% of beta-III tubulin-positive cells, only about 25% of nestin-positive precursor cells were MeCP2 positive. Further support for a correlation of MeCP2 expression with cell differentiation was observed in culture, where Western blot analysis during the in vitro differentiation of PC12, NG108-15, and SH-SY5Y cells revealed that MeCP2 levels increased as the cells acquired a more differentiated phenotype. This increase was associated with differentiation, as MeCP2 expression levels did not vary within different phases of the cell cycle. Taken together, these data support a role for MeCP2 in the establishment and/or maintenance of neuronal maturity.