Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice
Maria I. Bergamasco, Hannah K. Vanyai, Alexandra L. Garnham, Niall D. Geoghegan, Adam P. Vogel, Samantha Eccles, Kelly L. Rogers, Gordon K. Smyth, Marnie E. Blewitt, Anthony J. Hannan, Tim Thomas, Anne K. Voss
Maria I. Bergamasco, Hannah K. Vanyai, Alexandra L. Garnham, Niall D. Geoghegan, Adam P. Vogel, Samantha Eccles, Kelly L. Rogers, Gordon K. Smyth, Marnie E. Blewitt, Anthony J. Hannan, Tim Thomas, Anne K. Voss
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Research Article Development Genetics

Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice

Abstract

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/–), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/– mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/– mice and partially reversed gene expression changes in Kat6b+/– cortical neurons. Both compounds improved sociability in Kat6b+/– mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Authors

Maria I. Bergamasco, Hannah K. Vanyai, Alexandra L. Garnham, Niall D. Geoghegan, Adam P. Vogel, Samantha Eccles, Kelly L. Rogers, Gordon K. Smyth, Marnie E. Blewitt, Anthony J. Hannan, Tim Thomas, Anne K. Voss

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Figure 8

VPA treatment does not improve learning and memory in Kat6b+/– mice.

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VPA treatment does not improve learning and memory in Kat6b+/– mice. (A ...
(A and B) Proportion of time spent in the center of the open-field arena (A) and representative traces of movement in 5 minutes of the 20-minute testing time (B). (C and D) Total number of entries into the open arms (C) and distance traveled (D) in the elevated O maze. (E and F) Discrimination index for the novel over the familiar arm (E) and distance traveled in the Y maze for spatial memory (F). (G) Ratio of time spent around object 1 and object 2 or the novel and familiar object in the novel object–recognition test. (H–J) Number of errors before finding the target (H), deviation from the target at first error (I), and search strategy used (J) in the Barnes maze. n = 15–18 Kat6b+/+ (6–11M/6–9F) and 15 Kat6b+/– (5–8M/7–10F) mice per treatment group. Data are represented as mean ± SEM and were analyzed using 2-way (A, C, D, and F) or 3-way (G–J) ANOVA with Holm-Šidák correction or 1-sample t test comparing with 0 (E). Circles, triangles, individual female and male mice. Related data in Supplemental Figure 14.