Insights into the cellular and molecular contributions of MeCP2 overexpression to disease pathophysiology.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Dastidar et al. and Na et al. Rett syndrome (RTT) is a devastating and currently incurable neurodevelopmental disease that primarily affects females. RTT is caused by loss of the X-linked gene methyl-CpG-binding protein 2 (MECP2). The resulting decreases in MeCP2 protein levels lead to symptoms such as developmental regression , intellectual and learning difficulties , stereotyped hand motions, impaired motor skills, loss of language, ataxia, and seizures (Ramocki and Zoghbi, 2008). While there is evidence to suggest that the primary role of MeCP2 is transcriptional repression, it has also been shown to selectively enhance gene expression (Chahrour et al., 2008), and its specific roles in neuronal function remain controversial. Whereas much effort has been devoted to understanding the mechanisms of RTT pathology, relatively little is known regarding MECP2 duplication syndrome (MECP2 DS). In contrast to RTT, MECP2 DS affects mostly males and is caused by duplications of the MECP2 gene, which increases MeCP2 protein levels. MECP2 DS patients exhibit symptoms that, in some cases, resemble those seen in RTT, including mental retardation , impaired development of speech and motor control, and seizures (Ramocki and Zoghbi, 2008). However, recent work suggests that neurodegeneration may play a role in the pathology of MECP2 DS patients (Reardon et al., 2010), whereas neurodegen-eration has not thus far been associated with RTT. Two recent articles in The Journal of Neuroscience provide insight into MECP2 DS by characterizing animal and cell models of MeCP2 overexpression. Based on results from these studies, we present a hypothesis to link enhanced MeCP2 function to both synaptic deficits and neurodegeneration. Inthefirststudy,Naetal.(2012)character-ized a mouse model of MECP2 DS. Neuron-specific MeCP2 overexpression gave rise to animalswithdecreasedbodyweight,deficitsin motor coordination, increased anxiety-like behavior,andimpairedlearningandmemory, similar to symptoms observed in human MECP2 DS patients. Electrophysiological recordings in hippocampal brain slices from these mice revealed decreases in long-term potentiation (LTP) and the probability of neurotransmitter release, indicative of attenuated synapse strength and activity. Remarkably , administration of a histone deacetylase (HDAC) inhibitor reversed defects in miniature EPSCs observed in cultured hippocampal neurons, suggesting that HDAC-dependent transcriptional repression mediates synaptic defects associated with MeCP2 overexpression. Unexpectedly, …