Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Int J Neuropsychopharmacol. 2022 Oct 25;25(10):877-889. doi: 10.1093/ijnp/pyac048.
Microdeletion of the human 16p11.2 gene locus confers risk for autism spectrum disorders and intellectual disability. How 16p11.2 deletion is linked to these neurodevelopmental disorders and whether there are treatment avenues for the manifested phenotypes remain to be elucidated. Emerging evidence suggests that epigenetic aberrations are strongly implicated in autism.
We performed behavioral and electrophysiological experiments to examine the therapeutic effects of epigenetic drugs in transgenic mice carrying 16p11.2 deletion (16p11del/+).
We found that 16p11del/+ mice exhibited a significantly reduced level of histone acetylation in the prefrontal cortex (PFC). A short (3-day) treatment with class I histone deacetylase (HDAC) inhibitor MS-275 or Romidepsin led to the prolonged (3-4 weeks) rescue of social and cognitive deficits in 16p11del/+ mice. Concomitantly, MS-275 treatment reversed the hypoactivity of PFC pyramidal neurons and the hyperactivity of PFC fast-spiking interneurons. Moreover, the diminished N-methyl-D-aspartate (NMDA) receptor-mediated synaptic currents and the elevated GABAA receptor-mediated synaptic currents in PFC pyramidal neurons of 16p11del/+ mice were restored to control levels by MS-275 treatment.
Our results suggest that HDAC inhibition provides a highly effective therapeutic strategy for behavioral deficits and excitation/inhibition imbalance in 16p11del/+ mice, likely via normalization of synaptic function in the PFC.
人类 16p11.2 基因座的微缺失会增加自闭症谱系障碍和智力障碍的风险。16p11.2 缺失如何与这些神经发育障碍相关，以及是否有针对表现型的治疗途径，仍有待阐明。新出现的证据表明，表观遗传异常强烈地参与了自闭症。
我们进行了行为和电生理实验，以研究携带 16p11.2 缺失（16p11del/+）的转基因小鼠中表观遗传药物的治疗效果。
我们发现 16p11del/+ 小鼠前额叶皮层（PFC）中的组蛋白乙酰化水平显著降低。用 I 类组蛋白去乙酰化酶（HDAC）抑制剂 MS-275 或 Romidepsin 进行为期 3 天的短期治疗，可延长 16p11del/+ 小鼠的社交和认知缺陷的恢复时间（3-4 周）。同时，MS-275 治疗可逆转 PFC 锥体神经元的活动减少和 PFC 快速发射中间神经元的过度兴奋。此外，16p11del/+ 小鼠 PFC 锥体神经元中 NMDA 受体介导的突触电流减少和 GABAA 受体介导的突触电流升高可通过 MS-275 治疗恢复至对照水平。
我们的结果表明，HDAC 抑制为 16p11del/+ 小鼠的行为缺陷和兴奋/抑制失衡提供了一种非常有效的治疗策略，可能是通过 PFC 中突触功能的正常化来实现的。
