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Distinct contributions of three GABAergic interneuron populations to a mouse model of Rett Syndrome

James M. Mossner, Renata Batista-Brito, Rima Pant, Jessica A. Cardin
doi: https://doi.org/10.1101/155382
James M. Mossner
Department of Neuroscience, Yale University, New Haven CT 06520
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Renata Batista-Brito
Department of Neuroscience, Yale University, New Haven CT 06520
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Rima Pant
Department of Neuroscience, Yale University, New Haven CT 06520
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Jessica A. Cardin
Department of Neuroscience, Yale University, New Haven CT 06520
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Abstract

Background Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MeCP2. MeCP2 is a transcriptional regulator active in many cell types throughout the brain. However, mutations of MeCP2 restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a key role for inhibitory interneurons in the pathophysiology underlying this disorder.

Methods We generated conditional deletions of MeCP2 from each of three major classes of GABAergic interneurons, the parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP)-expressing cells, along with a pan-interneuron deletion from all three GABAergic populations. We examined seizure incidence, mortality, and performance on several key behavioral assays.

Results We find that each interneuron class makes a contribution to the seizure phenotype associated with Rett Syndrome. PV, SOM, and VIP interneurons made partially overlapping contributions to deficits in motor behaviors. We find little evidence for elevated anxiety associated with any of the conditional deletions. However, MeCP2 deletion from VIP interneurons causes a unique deficit in marble burying. Furthermore, VIP interneurons make a distinct contribution to deficits in social behavior.

Conclusions We find an unanticipated contribution of VIP interneuron dysfunction to the MeCP2 loss-of-function model of Rett Syndrome. Together, our findings suggest a complex interaction between GABAergic dysfunction and behavioral phenotypes in this neurodevelopmental disorder.

Footnotes

  • Financial disclosures: Authors report no biomedical financial interests or potential conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 25, 2017.
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Distinct contributions of three GABAergic interneuron populations to a mouse model of Rett Syndrome
James M. Mossner, Renata Batista-Brito, Rima Pant, Jessica A. Cardin
bioRxiv 155382; doi: https://doi.org/10.1101/155382
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Distinct contributions of three GABAergic interneuron populations to a mouse model of Rett Syndrome
James M. Mossner, Renata Batista-Brito, Rima Pant, Jessica A. Cardin
bioRxiv 155382; doi: https://doi.org/10.1101/155382

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