Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice

Abstract

Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.

Diminished social interaction incentive contributes to social deficits in mouse models of autism spectrum disorder

“…We thus speculate that the aversive pressure imposed by light exposure alone in LDB is insufficient to suppress the drive for social reward in Shank3 +/ΔC and BTBR mice. There is an apparent contradiction as Shank3 +/ΔC mice display social withdrawal symptoms in the social approach test 17 In the modified EPM protocols, Shank3 +/ΔC and BTBR mice displayed a significantly lower SII in the social incentive trial than the object incentive trial, suggesting that in these ASD models, the incentive to engage in an interaction with a novel object may exceed that of a social stimulus. However, the SII for WT animals did not differ between the object-and social-incentive trials, which appears in contrast to 3-chamber social preference findings in which WT animals routinely demonstrate a significant preference for the social stimulus over a novel object.…”

“…Sample sizes were based on power analyses with current sample size providing a power of 0.95 for P < .05, which were similar to those reported previously. 17 Data in figures are presented as mean ± SEM. F values, degrees of freedom, and P values for all ANOVAs, as well as t values and degrees of freedom for t tests, are included within the text for all statistical analyses performed.…”

“…However, the SII for WT animals did not differ between the object-and social-incentive trials, which appears in contrast to 3-chamber social preference findings in which WT animals routinely demonstrate a significant preference for the social stimulus over a novel object. 16,17 We theorize that the lack of difference between the WT object-and social-stimulus incentive indexes is due to differences in testing parameters between the traditional 3-chamber paradigm and the EPM models used here. Principally, the 3-chamber paradigm exposes the test mouse to a social stimulus and a novel object simultaneously, forcing the test animal to actively choose to interact with one stimulus over the other, which typically results in a time distribution favoring the social stimulus over the object.…”

Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex

“…In the present study, we investigated whether the loss-offunction of CNTNAP2 or AHI1 resulted in common phenotypes of synaptic dysfunction and ASD-related behavior in mice. We performed knockdown of CNTNAP2 or AHI1 in layer 2/3 pyramidal neurons of the mouse prefrontal cortex (PFC), which has been implicated in social behavior and ASD 23,[34][35][36][37][38][39][40][41][42][43] . We found that knockdown of CNTNAP2 in layer 2/3 pyramidal neurons of the PFC reduced excitatory and inhibitory synaptic transmission presumably by decreasing the number of functional synapses, elevated inhibition/excitation (I/E) balance, impaired social interaction, and induced mild pup vocalization abnormality.…”

Altered synaptic ultrastructure in the prefrontal cortex of Shank3-deficient rats

“…A study in the mouse brain found that proteins interacting with Shank3 in the PFC are different from those in the hippocampus and striatum (93). PFC-speci c epigenetic modi cations of histones, such as higher dimethylation (94) and lower acetylation (95) in Shank3-Het mice with an exon 21 deletion and higher dimethylation in postmortem ASD brains (94), suggest a brain region-speci c mechanism for regulation of protein expression. Notably, the expression of Shank3 is highest in the PFC compared to other regions in the macaque brain (75), whereas Shank3 isoforms containing ANK domain are highly expressed in the upper cortical layers, hippocampus and striatum of the mouse brain (96).…”