{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:12:52Z","timestamp":1785161572464,"version":"3.55.0"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T00:00:00Z","timestamp":1734480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sanford School of Medicine, University of South Dakota","award":["R21 MH134106"],"award-info":[{"award-number":["R21 MH134106"]}]},{"name":"Sanford School of Medicine, University of South Dakota","award":["P30 GM154633"],"award-info":[{"award-number":["P30 GM154633"]}]},{"name":"Sanford School of Medicine, University of South Dakota","award":["P20 GM103443"],"award-info":[{"award-number":["P20 GM103443"]}]},{"name":"Sanford School of Medicine Faculty Research Grant","award":["R21 MH134106"],"award-info":[{"award-number":["R21 MH134106"]}]},{"name":"Sanford School of Medicine Faculty Research Grant","award":["P30 GM154633"],"award-info":[{"award-number":["P30 GM154633"]}]},{"name":"Sanford School of Medicine Faculty Research Grant","award":["P20 GM103443"],"award-info":[{"award-number":["P20 GM103443"]}]},{"name":"South Dakota Board of Regents Competitive Research Grant","award":["R21 MH134106"],"award-info":[{"award-number":["R21 MH134106"]}]},{"name":"South Dakota Board of Regents Competitive Research Grant","award":["P30 GM154633"],"award-info":[{"award-number":["P30 GM154633"]}]},{"name":"South Dakota Board of Regents Competitive Research Grant","award":["P20 GM103443"],"award-info":[{"award-number":["P20 GM103443"]}]},{"name":"NIH","award":["R21 MH134106"],"award-info":[{"award-number":["R21 MH134106"]}]},{"name":"NIH","award":["P30 GM154633"],"award-info":[{"award-number":["P30 GM154633"]}]},{"name":"NIH","award":["P20 GM103443"],"award-info":[{"award-number":["P20 GM103443"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: ASH1L (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal Ash1l severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, the synaptic mechanisms underlying autism-like social deficits and seizures need to be elucidated. Objective: The goal of this study is to characterize the behavioral deficits and reveal the synaptic mechanisms in an Ash1l haploinsufficiency mouse model using a targeted gene-trap knockout (gtKO) strategy. Method: A series of behavioral tests were used to examine behavioral deficits. Electrophysiological and chemogenetic approaches were used to examine and manipulate the excitability of pyramidal neurons in the PFC of Ash1l+\/GT mice. Results: Ash1l+\/GT mice displayed social deficits, increased self-grooming, and cognitive impairments. Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+\/GT mice, indicating absence-like seizures. Ash1l haploinsufficiency increased the susceptibility for convulsive seizures when Ash1l+\/GT mice were challenged by pentylenetetrazole (PTZ, a competitive GABAA receptor antagonist). Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition. Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l+\/GT mice ameliorated autism-like social deficits and abolished absence-like seizures. Conclusions: We demonstrated that increased neural activity in the PFC contributed to the autism-like social deficits and absence-like seizures in Ash1l+\/GT mice, which provides novel insights into the therapeutic strategies for patients with ASH1L-associated ASD and epilepsy.<\/jats:p>","DOI":"10.3390\/genes15121619","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T08:56:32Z","timestamp":1734512192000},"page":"1619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6355-4952","authenticated-orcid":false,"given":"Kaijie","family":"Ma","sequence":"first","affiliation":[{"name":"Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kylee","family":"McDaniel","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Mount Marty University, Yankton, SD 57078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Webb","sequence":"additional","affiliation":[{"name":"School of Health Sciences, University of South Dakota, Vermillion, SD 57069, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luye","family":"Qin","sequence":"additional","affiliation":[{"name":"Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/aur.1514","article-title":"Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased Risk for Females","volume":"9","author":"Blackmon","year":"2016","journal-title":"Autism Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Frye, R.E., Rossignol, D., Casanova, M.F., Brown, G.L., Martin, V., Edelson, S., Coben, R., Lewine, J., Slattery, J.C., and Lau, C. 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