Rescue of behavioral and EEG deficits in male and female Mecp2-deficient mice by delayed Mecp2 gene reactivation

Abstract

Mutations of the X-linked gene encoding methyl CpG binding protein type 2 (MECP2) are the predominant cause of Rett syndrome, a severe neurodevelopmental condition that affects primarily females. Previous studies have shown that major phenotypic deficits arising from MeCP2-deficiency may be reversible, as the delayed reactivation of the Mecp2 gene in Mecp2-deficient mice improved aspects of their Rett-like phenotype. While encouraging for prospective gene replacement treatments, it remains unclear whether additional Rett syndrome co-morbidities recapitulated in Mecp2-deficient mice will be similarly responsive to the delayed reintroduction of functional Mecp2. Here, we show that the delayed reactivation of Mecp2 in both male and female Mecp2-deficient mice rescues established deficits in motor and anxiety-like behavior, epileptiform activity, cortical and hippocampal electroencephalogram patterning and thermoregulation. These findings indicate that neural circuitry deficits arising from the deficiency in Mecp2 are not engrained, and provide further evidence that delayed restoration of Mecp2 function can improve a wide spectrum of the Rett-like deficits recapitulated by Mecp2-deficient mice.

Clinical and biological progress over 50 years in Rett syndrome

“…185 Approaches targeting MeCP2 at the level of the gene or protein to restore functional MeCP2 within the nervous system are appealing in that they have the potential to produce a profound amelioration or reversal of symptoms based on reversal studies in mice. 43,44,189 Such approaches involve molecular and genetic manipulations ranging from gene transfer 190,191 and protein substitution to novel forms of DNA and RNA editing. 192 However, the level of MeCP2 in a given cell may be critical 193 and restoring MeCP2 function without producing overexpression-related pathology is likely to be a significant challenge.…”

Loss of MeCP2 in cholinergic neurons causes part of RTT-like phenotypes via α7 receptor in hippocampus

“…Deletion of Mecp2 from different neuronal types in various brain regions can produce different phenotypes of RTT [15][16][17][18][19][20]. Subsequent reactivation of Mecp2 in Mecp2-deficient mice also substantially improves behavioral and cellular deficits, suggesting that impaired circuitry in a Mecp2-deficient brain can be restored [21][22][23]. In addition, recent studies have demonstrated that treatment with clenbuterol, an agonist for adrenergic receptors, npg www.cell-research.com | Cell Research improves survival and ameliorates diverse phenotypes in Mecp2 mutant mice [24].…”

A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice

“…One feature commonly associated with the absence of MeCP2 is neural network hyper-excitability Calfa et al, 2011;Ward et al, 2011;McLeod et al, 2013). We have previously reported rhythmic cortical spike and wave EEG discharges in both male and female mice expressing a null Mecp2 allele (D'Cruz et al, 2010;Wither et al, 2012;Lang et al, 2014). Shahbazian et al (2002) also reported myoclonic jerks coupled with high-amplitude bilateral cortical spike and wave discharges in the Mecp2 308/y mouse, and Goffin et al (2011) reported evidence for cortical network hyper-excitability in the Mecp2 T158A/y mouse model.…”

“…Concordance rates between the two counters were greater than 90%. Excitatory discharge events were defined as rhythmic spike waveforms, having amplitudes of at least 1.5-fold background, durations of at least 0.4 s, and frequencies between 6 and 10 Hz (D'Cruz et al, 2010;Wither et al, 2012Wither et al, , 2013Lang et al, 2013Lang et al, , 2014. Long discharge events were defined similarly to typical discharge events, but required a minimum duration of 5 s and an average frequency of between 4 and 6 Hz.…”