Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome.

Kerstin Ure,Ling-Jie He,Wu Chen,Aya Ito-Ishida,Yehezkel Sztainberg,Jianrong Tang,Wei Wang,Zhenyu Wu,Hui Lu,Huda Y Zoghbi

doi:10.7554/elife.14198

Kerstin Ure, Ling-Jie He + Show 8 more

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https://doi.org/10.7554/elife.14198

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Abstract

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

Highlights

Maintaining a proper ratio of excitation and inhibition throughout the brain is critical to normal neurological function
At the time of this writing, there have been several conditional knockouts of Mecp2 that target different neuronal subtypes, each replicating a few aspects of the Mecp2 deletion phenotype: Sim1 conditional knockout mice are hyperphagic and become obese (Fyffe et al, 2008); mice with Mecp2 deleted from dopaminergic neurons develop some motor deficits (Samaco et al, 2009); and conditional knockout of Mecp2 from basal forebrain cholinergic neurons may result in Neuroscience decreased anxiety and impaired social interaction (Zhang et al, 2016)
Of all the conditional knockouts, the GABAergic conditional knockout mouse most closely replicates the effect of global Mecp2 deletion, with premature lethality, motor dysfunction, learning and memory deficits, and stereotypies

Summary

Introduction

Maintaining a proper ratio of excitation and inhibition throughout the brain is critical to normal neurological function. Alterations in this excitatory/inhibitory balance are postulated to underlie a number of neuropsychiatric disorders, such as autism (Vattikuti and Chow, 2010; Gogolla et al, 2009; Rubenstein and Merzenich, 2003), schizophrenia (Belforte et al, 2010), and Rett syndrome (Dani et al, 2005). Dysfunctional GABAergic signaling has been implicated in multiple neurological and neuropsychiatric disorders (Siniatchkin and Koepp, 2009; Pizzarelli and Cherubini, 2011), including Rett syndrome (Chao et al, 2010). RTT is notable for the variety of different behaviors it affects: disease-causing MECP2 mutations cause a rapidly fatal neonatal encephalopathy

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