mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model

Publication date: Available online 9 November 2018Source: Pharmacology Biochemistry and BehaviorAuthor(s): Haruki Kawase, Yukio Ago, Megumi Naito, Momoko Higuchi, Yuta Hara, Shigeru Hasebe, Shinji Tsukada, Atsushi Kasai, Takanobu Nakazawa, Tadashi Mishina, Hiroyuki Kouji, Kazuhiro Takuma, Hitoshi HashimotoAbstractGrowing evidence suggests pivotal roles for epigenetic mechanisms in both animal models of and individuals with autism spectrum disorders (ASD). Neuron-restrictive silencer factor (NRSF) binds to neuron-restrictive silencing elements in neuronal genes and recruits co-repressors, such as mSin3, to epigenetically inhibit neuronal gene expression. Because dysregulation of NRSF is related to ASD, here we examined the effects of mS-11, a chemically optimized mimetic of the mSin3-binding helix in NRSF, on the behavioral and morphological abnormalities found in a mouse model of valproic acid (VPA)-induced ASD. Chronic treatment with mS-11 improved prenatal VPA-induced deficits in social interaction. Additionally, we found that NRSF mRNA expression was greater in the somatosensory cortex of VPA-exposed mice than of controls. Agreeing with these behavioral findings, mice that were prenatally exposed to VPA showed lower dendritic spine density in the somatosensory cortex, which was reversed by chronic treatment with mS-11. These findings suggest that mS-11 has the potential for improving ASD-related symptoms through inhibition of mSin3-NRSF binding.
Source: Pharmacology Biochemistry and Behavior - Category: Biochemistry Source Type: research