Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice

Kerr, Bredford; Alvarez-Saavedra, Matías; Sáez, Mauricio; Saona, Alexandra; Young, Juan I.

doi:10.1093/hmg/ddn061

Cited by 67 publications

(57 citation statements)

References 48 publications

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“…24,29 This apparent inconsistency could be due to small differences in patterns of transgene expression, or to the different time point in which the mice were tested (7 weeks of age (this study) versus 12 weeks). Also, subtle phenotypic manifestations not analyzed in this study, such as social behavior, could still be present in Mecp2 À/y mice expressing transgenic MeCP2-e1.…”

Section: Discussionmentioning

confidence: 94%

“…24,25 Thus, we determined the level of expression of transgenic MeCP2 by comparing the immunoreactivity for MeCP2 in protein extracts obtained from a variety of brain regions of transgenic and wild-type mice. Analysis of the western blot results indicated that expression of MeCP2-e1 in e1-TgH and e1-TgL varied between brain regions, averaging at 40 and 15% of MeCP2 wild-type expression, respectively (data not shown).…”

Section: Expression Of Isoform-specific Cdnas In Transgenic Micementioning

confidence: 99%

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Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

Kerr

Sáez

et al. 2011

Eur J Hum Genet

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Rett syndrome (RTT) is a disorder that affects patients' ability to communicate, move and behave. RTT patients are characterized by impaired language, stereotypic behaviors, frequent seizures, ataxia and sleep disturbances, with the onset of symptoms occurring after a period of seemingly normal development. RTT is caused by mutations in methyl-CpG binding protein 2 (MECP2), an X-chromosome gene encoding for MeCP2, a protein that regulates gene expression. MECP2 generates two alternative splice variants encoding two protein isoforms that differ only in the N-terminus. Although no functional differences have been identified for these splice variants, it has been suggested that the RTT phenotype may occur in the presence of a functional MeCP2-e2 protein. This suggests that the two isoforms might be functionally distinct. Supporting this notion, the two variants show regional and age-related differences in transcript abundance. Here, we show that transgenic expression of either the MeCP2-e1 or MeCP2-e2 splice variant results in prevention of development of RTT-like phenotypic manifestations in a mouse model lacking Mecp2. Our results indicate that the two MeCP2 splice variants can substitute for each other and fulfill the basic functions of MeCP2 in the mouse brain.

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Section: Discussionmentioning

confidence: 94%

Section: Expression Of Isoform-specific Cdnas In Transgenic Micementioning

confidence: 99%

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

Kerr

Sáez

et al. 2011

Eur J Hum Genet

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“…We removed Mecp2 from cholinergic neurons by breeding mice carrying a Mecp2 allele flanked by loxp sites (Mecp2 flox/− ) [30] with Cre transgenic (Chat-IRESCre) mice (Supplementary information, Figure S1A). To determine Mecp2 deletion in cholinergic neurons, we stained BF sections with MeCP2 and ChAT, a marker for cholinergic neurons ( Figure 1A).…”

Section: Selective Deletion Of Mecp2 In Cholinergic Neurons Led To Pamentioning

confidence: 99%

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

et al. 2016

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Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2 −/y ) mice. We found that choline acetyltransferase expression was decreased in the BF and that α7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2 −/y mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2 −/y mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.

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“…In this regard, relatively subtle decreases in MeCP2 expression are sufficient to induce behavioral impairments in mice (Samaco et al, 2008;Kerr et al, 2008), and decreases in brain MeCP2 levels have been reported in neurological conditions such as Angelman syndrome, attention deficit hyperactivity disorder, and general autism (Nagarajan et al, 2006;Neul, 2012;Gonzales and LaSalle, 2010). Thus, the neural link we illustrate here between MeCP2 and GAT-1 expression may be worthy of assessment in other conditions in which imbalances of excitatory and inhibitory tone are believed to have a role in pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Wither

Lang

et al. 2015

Neuropsychopharmacol

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Cortical network hyper-excitability is a common phenotype in mouse models lacking the transcriptional regulator methyl-CPG-binding protein 2 (MeCP2). Here, we implicate enhanced GABA B receptor activity stemming from diminished cortical expression of the GABA transporter GAT-1 in the genesis of this network hyper-excitability. We found that administering the activity-dependent GABA B receptor allosteric modulator GS-39783 to female Mecp2 +/ − mice at doses producing no effect in wild-type mice strongly potentiated their basal rates of spontaneous cortical discharge activity. Consistently, administering the GABA B receptor antagonist CGP-35348 significantly decreased basal discharge activity in these mice. Expression analysis revealed that while GABA B or extra-synaptic GABA A receptor prevalence is preserved in the MeCP2-deficient cortex, the expression of GAT-1 is significantly reduced from wild-type levels. This decrease in GAT-1 expression is consequential, as low doses of the GAT-1 inhibitor NO-711 that had no effects in wild-type mice strongly exacerbated cortical discharge activity in female Mecp2 +/ − mice. Taken together, these data indicate that the absence of MeCP2 leads to decreased cortical levels of the GAT-1 GABA transporter, which facilitates cortical network hyper-excitability in MeCP2-deficient mice by increasing the activity of cortical GABA B receptors.

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Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice

Cited by 67 publications

References 48 publications

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes

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

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

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