A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice

Author:

Medeiros Destynie12,Ayala-Baylon Karen12,Egido-Betancourt Hailey12,Miller Eric12,Chapleau Christopher12,Robinson Holly12,Phillips Mary L.12,Yang Tao3,Longo Frank M.3,Li Wei12,Pozzo-Miller Lucas12ORCID

Affiliation:

1. School of Medicine 1 Department of Neurobiology , , , Birmingham, AL 35294 , USA

2. University of Alabama at Birmingham 1 Department of Neurobiology , , , Birmingham, AL 35294 , USA

3. Stanford University School of Medicine 2 Department of Neurology and Neurological Sciences , , Stanford, CA 94305 , USA

Abstract

ABSTRACT Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

Funder

National Institutes of Health

National Institute of Child Health and Human Development

National Institute of Mental Health

National Institute of Neurological Disorders and Stroke

Rett Syndrome Research Trust

Publisher

The Company of Biologists

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Translating multiscale research in rare disease;Disease Models & Mechanisms;2024-06-01

2. First person – Destynie Medeiros;Disease Models & Mechanisms;2024-05-24

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