Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome.

Kabuki syndrome is caused by haploinsufficiency for either of two genes that promote the opening of chromatin. If an imbalance between open and closed chromatin is central to the pathogenesis of Kabuki syndrome, agents that promote chromatin opening might have therapeutic potential. We have characterized a mouse model of Kabuki syndrome with a heterozygous deletion in the gene encoding the lysine-specific methyltransferase 2D (Kmt2d), leading to impairment of methyltransferase function. In vitro reporter alleles demonstrated a reduction in histone 4 acetylation and histone 3 lysine 4 trimethylation (H3K4me3) activity in mouse embryonic fibroblasts from Kmt2d(+/ßGeo) mice. These activities were normalized in response to AR-42, a histone deacetylase inhibitor. In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/ßGeo) mice correlated with reduced neurogenesis and hippocampal memory defects. These abnormalities improved upon postnatal treatment with AR-42. Our work suggests that a reversible deficiency in postnatal neurogenesis underlies intellectual disability in Kabuki syndrome.

Increased intra-individual reaction time variability in attention-deficit/hyperactivity disorder across response inhibition tasks with different cognitive demands.

One of the most consistent findings in children with ADHD is increased moment-to-moment variability in reaction time (RT). The source of increased RT variability can be examined using ex-Gaussian analyses that divide variability into normal and exponential components and Fast Fourier transform (FFT) that allow for detailed examination of the frequency of responses in the exponential distribution. Prior studies of ADHD using these methods have produced variable results, potentially related to differences in task demand. The present study sought to examine the profile of RT variability in ADHD using two Go/No-go tasks with differing levels of cognitive demand. A total of 140 children (57 with ADHD and 83 typically developing controls), ages 8-13 years, completed both a "simple" Go/No-go task and a more "complex" Go/No-go task with increased working memory load. Repeated measures ANOVA of ex-Gaussian functions revealed for both tasks children with ADHD demonstrated increased variability in both the normal/Gaussian (significantly elevated sigma) and the exponential (significantly elevated tau) components. In contrast, FFT analysis of the exponential component revealed a significant task x diagnosis interaction, such that infrequent slow responses in ADHD differed depending on task demand (i.e., for the simple task, increased power in the 0.027-0.074 Hz frequency band; for the complex task, decreased power in the 0.074-0.202 Hz band). The ex-Gaussian findings revealing increased variability in both the normal (sigma) and exponential (tau) components for the ADHD group, suggest that both impaired response preparation and infrequent "lapses in attention" contribute to increased variability in ADHD. FFT analyses reveal that the periodicity of intermittent lapses of attention in ADHD varies with task demand. The findings provide further support for intra-individual variability as a candidate intermediate endophenotype of ADHD.