Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett Syndrome

Abstract

Rett Syndrome (RTT) is a devastating neurological disorder that is caused by mutations in the MECP2 gene. Mecp2-mutant mice have been used as a model system to study the disease mechanism. Our previous work has suggested that MeCP2 malfunction in neurons is the primary cause of RTT in the mouse. However, the neurophysiological consequences of MeCP2 malfunction remain obscure. Using whole-cell patch-clamp recordings in cortical slices, we show that spontaneous activity of pyramidal neurons is reduced in Mecp2-mutant mice. This decrease is not caused by a change in the intrinsic properties of the recorded neurons. Instead, the balance between cortical excitation and inhibition is shifted to favor inhibition over excitation. Moreover, analysis of the miniature excitatory postsynaptic currents (mEPSCs)͞inhibitory postsynaptic currents (mIPSCs) in the Mecp2-mutant cortex reveals a reduction in mEPSC amplitudes, without significant change in the average mIPSC amplitude or frequency. These findings provide the first detailed electrophysiological analysis of Mecp2-mutant mice and provide a framework for understanding the pathophysiology of the disease and tools for studying the underlying disease mechanisms.autism ͉ cortical circuit ͉ MeCP2 ͉ mental retardation R ett Syndrome (RTT) is a pervasive neurodevelopmental disorder associated with mental retardation, autistic behavior, and loss of previously acquired skills, including purposeful hand use and expressive language (1). Affected individuals begin to acquire motor and cognitive function normally but then regress after 6-18 months. The disease is sex-linked and is due, in most cases, to abnormal function of a single gene, the methyl CpG-binding protein MECP2 (2). Deletion of all, or the third exon, of the Mecp2 gene produces functional nulls and recapitulates, in mice, many features of the human disorder (3, 4). Mice with truncated MeCP2 also recapitulate many RTT features (5). Mecp2-null mice are normal until 5 weeks of age, when they begin to exhibit abnormal behavior resembling symptoms observed in RTT patients. Brain-specific Mecp2-mutant mice show pathological symptoms identical to those found in the germline Mecp2-null mice, thereby implicating MeCP2 malfunction in the brain as the primary cause of RTT (3). Transgenic expression of MeCP2 in postmitotic neurons in the Mecp2-mutant mice rescues the RTT phenotype (6). Overexpression of MeCP2 in postmitotic neurons in WT mice also causes behavioral and physiological abnormalities (6, 7). Taken together, these data strongly argue for the importance of MeCP2 function during the normal maturation and refinement of neural circuits, which may be compromised in Mecp2-mutant mice.Despite profound behavioral abnormalities and premature death, the neuropathological phenotype is remarkably subtle in Mecp2-mutant mice. The mutant brain weighs Ϸ20-25% less than the WT. Mutant hippocampal CA2 pyramidal neurons are Ϸ15-25% smaller than WT neurons (3). Mutant neocortical projection neurons have simplified dendritic arbors (8). Ye...

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“…Additionally, mutations in cyclin-dependent kinase-like 5 (Cdkl5) also produce Rett-like syndrome. The neuropathologies in the MeCP2 KO model of Rett syndrome include a reduction in dendritic spine density, lower glutamatergic synapses, and a shift in excitatoryinhibitory balance toward greater inhibition (Dani et al, 2005;Nelson et al, 2006;Chao et al, 2007;Blackman et al, 2012;Na et al, 2013). Reduction in spine density is also observed in brains from Rett syndrome patients (Chapleau et al, 2009).…”

The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome

“…It could also be explained by an as yet untested possibility that the two proteins (MeCP2 and BDNF) have certain overlapping effects. In addition, it could be that MeCP2 dysfunction reduces overall neuronal activity, thereby indirectly resulting in decreased BDNF, 36 further accentuating possible adverse effects of a less efficient BDNF protein variant. On the other hand, it could also suggest a direct role of MeCP2 protein in BDNF gene expression, and as a consequence a significant role of Bdnf/BDNF protein activity in the pathogenesis of RTT in both the mouse model and the human.…”

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“…The authors attributed this change to a shift toward reduced cortical excitability and an enhanced inhibitory drive in the model of Rett syndrome, rather than to any intrinsic anomaly in the neurons themselves. 125 Ca þ 2 /calmodulin-dependent protein kinase II (CaMKII) is an important mediator of LTP [126][127][128][129][130] and other forms of synaptic plasticity. 131 Stimuli that induce LTP also persistently activate CaMKII, which may be critical for the molecular memory of synaptic events.…”