Effects of early-life exposure to THIP on brainstem neuronal excitability in the Mecp2
-null mouse model of Rett syndrome before and after drug withdrawal

Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder<xref ref-type="bibr" rid="bib19"/><xref ref-type="bibr" rid="bib15"/><xref ref-type="bibr" rid="bib37"/><xref ref-type="bibr" rid="bib47"/>. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role<xref ref-type="bibr" rid="bib67"/>. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.

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Lung abnormalities in MECP2-null mouse model of Rett syndrome

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.2596 ◽

2017 ◽

Vol 381 ◽

pp. 923

Author(s):

H. Kida ◽

T. Takahashi ◽

Y. Nakamura ◽

T. Kinoshita ◽

S. Okayama ◽

...

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Null Mouse ◽

Lung Abnormalities

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Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome

Human Molecular Genetics ◽

10.1093/hmg/ddaa102 ◽

2020 ◽

Vol 29 (15) ◽

pp. 2461-2470

Author(s):

Jonathan K Merritt ◽

Bridget E Collins ◽

Kirsty R Erickson ◽

Hongwei Dong ◽

Jeffrey L Neul

Keyword(s):

Mouse Model ◽

Rett Syndrome ◽

Therapeutic Approach ◽

Neurodevelopmental Disorder ◽

Intraperitoneal Administration ◽

Full Length ◽

Nonsense Suppression ◽

Null Mouse ◽

Peripheral Tissues ◽

Mecp2 Protein

Abstract Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.

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