抑制组蛋白去甲基化酶LSD1可改善adnp突变小鼠的突触缺陷

IF 5.6 2区 医学 Q1 BEHAVIORAL SCIENCES
Autism Research Pub Date : 2025-06-19 DOI:10.1002/aur.70069
Chih-Hung Lin, Yong Ren, Kin Wai Tam, Megan Conrow-Graham, Zhen Yan
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引用次数: 0

摘要

ADNP(活性依赖性神经保护蛋白)是自闭症高危基因。在这里,我们研究了携带自闭症Adnp c端突变(Adnpmut)的杂合小鼠的突触改变。我们发现Adnpmut小鼠PFC锥体神经元的谷氨酸能和gaba能突触传递明显减少,这表明兴奋性突触后电流(EPSC)和抑制性突触后电流(IPSC)明显减少。鉴于ADNP在染色质调控中的关键作用以及ADNP复合物与赖氨酸特异性去甲基酶1 (LSD1)的组成性关联,我们研究了抑制LSD1对Adnpmut小鼠的治疗效果。我们发现LSD1抑制剂显著提高Adnpmut小鼠PFC锥体神经元的EPSC和IPSC,且在雌性小鼠中拯救作用尤为突出。生化分析显示,LSD1抑制剂处理后雌性Adnpmut小鼠H3K4me2升高,H3K9me2/3降低,这与处理后与谷氨酸能和gaba能传递相关的突触基因表达升高有关。这些数据揭示了由Adnp功能缺失突变引起的PFC突触缺陷,并揭示了LSD1抑制在Adnp缺陷条件下的治疗潜力,特别是对女性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synaptic Deficits in Adnp-Mutant Mice Are Ameliorated by Histone Demethylase LSD1 Inhibition

ADNP (Activity-dependent neuroprotective protein) is a top-ranking autism risk gene. Here we examined synaptic alterations in heterozygous mice carrying an autism mutation on Adnp C-terminus (Adnpmut). We found that PFC pyramidal neurons in Adnpmut mice exhibited significantly diminished glutamatergic and GABAergic synaptic transmission, as indicated by markedly reduced excitatory postsynaptic currents (EPSC) and inhibitory postsynaptic currents (IPSC). Given the key role of ADNP in chromatin regulation and the constitutive association of the ADNP complex with lysine-specific demethylase 1 (LSD1), we examined the therapeutic effects of LSD1 inhibition in Adnpmut mice. We found that treatment with an LSD1 inhibitor significantly elevated EPSC and IPSC in PFC pyramidal neurons of Adnpmut mice, and the rescuing effect was particularly prominent in females. Biochemical assays revealed increased H3K4me2 and decreased H3K9me2/3 by LSD1 inhibitor treatment in female Adnpmut mice, which were correlated with the elevated expression of synaptic genes linked to glutamatergic and GABAergic transmission after the treatment. These data have revealed synaptic deficits in PFC induced by a loss-of-function mutation of Adnp and uncovered the therapeutic potential of LSD1 inhibition in ADNP-deficient conditions, especially for females.

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来源期刊
Autism Research
Autism Research 医学-行为科学
CiteScore
8.00
自引率
8.50%
发文量
187
审稿时长
>12 weeks
期刊介绍: AUTISM RESEARCH will cover the developmental disorders known as Pervasive Developmental Disorders (or autism spectrum disorders – ASDs). The Journal focuses on basic genetic, neurobiological and psychological mechanisms and how these influence developmental processes in ASDs.
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