Chih-Hung Lin, Yong Ren, Kin Wai Tam, Megan Conrow-Graham, Zhen Yan
{"title":"抑制组蛋白去甲基化酶LSD1可改善adnp突变小鼠的突触缺陷","authors":"Chih-Hung Lin, Yong Ren, Kin Wai Tam, Megan Conrow-Graham, Zhen Yan","doi":"10.1002/aur.70069","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p><i>ADNP</i> (Activity-dependent neuroprotective protein) is a top-ranking autism risk gene. Here we examined synaptic alterations in heterozygous mice carrying an autism mutation on <i>Adnp</i> C-terminus (<i>Adnp</i><sup>mut</sup>). We found that PFC pyramidal neurons in <i>Adnp</i><sup>mut</sup> 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 <i>Adnp</i><sup>mut</sup> mice. We found that treatment with an LSD1 inhibitor significantly elevated EPSC and IPSC in PFC pyramidal neurons of <i>Adnp</i><sup>mut</sup> 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 <i>Adnp</i><sup>mut</sup> 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 <i>Adnp</i> and uncovered the therapeutic potential of LSD1 inhibition in ADNP-deficient conditions, especially for females.</p>\n </div>","PeriodicalId":131,"journal":{"name":"Autism Research","volume":"18 7","pages":"1342-1355"},"PeriodicalIF":5.6000,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synaptic Deficits in Adnp-Mutant Mice Are Ameliorated by Histone Demethylase LSD1 Inhibition\",\"authors\":\"Chih-Hung Lin, Yong Ren, Kin Wai Tam, Megan Conrow-Graham, Zhen Yan\",\"doi\":\"10.1002/aur.70069\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p><i>ADNP</i> (Activity-dependent neuroprotective protein) is a top-ranking autism risk gene. Here we examined synaptic alterations in heterozygous mice carrying an autism mutation on <i>Adnp</i> C-terminus (<i>Adnp</i><sup>mut</sup>). We found that PFC pyramidal neurons in <i>Adnp</i><sup>mut</sup> 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 <i>Adnp</i><sup>mut</sup> mice. We found that treatment with an LSD1 inhibitor significantly elevated EPSC and IPSC in PFC pyramidal neurons of <i>Adnp</i><sup>mut</sup> 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 <i>Adnp</i><sup>mut</sup> 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 <i>Adnp</i> and uncovered the therapeutic potential of LSD1 inhibition in ADNP-deficient conditions, especially for females.</p>\\n </div>\",\"PeriodicalId\":131,\"journal\":{\"name\":\"Autism Research\",\"volume\":\"18 7\",\"pages\":\"1342-1355\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-06-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Autism Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/aur.70069\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BEHAVIORAL SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Autism Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/aur.70069","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
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.
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.