Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
Kaijie MaZhen Yan

Abstract

Autism is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Genetic screening has identified synaptic, transcriptional, and chromatin genes disrupted in autistic patients. Haploinsufficiency of Shank3, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism. Using a Shank3-deficient mouse model that exhibits prominent autism-like phenotypes, we have found that histone acetylation in the prefrontal cortex (PFC) is abnormally low, which can be reversed by MS-275 (also known as Entinostat, SNDX-275), a class I histone deacetylase (HDAC) inhibitor that is selectively potent in PFC. A brief (3-day) treatment with MS-275 (i.p.) led to the sustained (11 days) rescue of autistic social preference deficits in Shank3-deficient mice, without altering locomotion, motor coordination, anxiety, or the increased grooming. MS-275 treatment also rescued the diminished NMDAR surface expression and NMDAR function induced by Shank3 deficiency. Moreover, F-actin at synapses was restored and the transcription of actin regulators was elevated by MS-275 treatment of Shank3-deficient mice, which may contribute to the recovery of actin-based NMDAR synaptic delivery. Taken together, t...Continue Reading

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Citations

Feb 9, 2020·Molecular Psychiatry·Yan KongZheng Sun
Nov 19, 2020·Molecular Autism·Sarah Jacot-DescombesMerina Varghese
Jan 21, 2021·Molecular Autism·Emmanuel MatasMohamed Jaber
Jun 27, 2021·Pharmacology & Therapeutics·Danielle Baribeau, Evdokia Anagnostou
Oct 2, 2021·Frontiers in Molecular Neuroscience·Ye-Eun YooEunjoon Kim

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Methods Mentioned

BETA
histone acetylation
PCR
transfection
immunoprecipitation
ChIP
transfections
nucleotide exchange
acetylation
exome sequencing

Software Mentioned

Clampex
Clampfit
GraphPad Prism

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