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Clinical studies for SZ are currently in phase \u0399\u0399\u0399 for SEP\u2010363856 (SEP\u2010856)\u2010a new antipsychotic that doesn't work on dopamine D\n                    <jats:sub>2<\/jats:sub>\n                    receptors. However, the underlying action mechanism of SEP\u2010856 remains unknown. This study aimed to evaluate the impact and underlying mechanisms of SEP\u2010856 on SZ\u2010like behavior in a perinatal MK\u2010801 treatment combined with social isolation from the weaning to adulthood model (MK\u2010SI). First, we created an animal model that resembles SZ that combines the perinatal MK\u2010801 with social isolation from weaning to adulthood. Then, different classical behavioral tests were used to evaluate the antipsychotic properties of SEP\u2010856. The levels of proinflammatory cytokines (tumor necrosis factor\u2010\u03b1, interleukin\u20106, and interleukin\u20101\u03b2), apoptosis\u2010related genes (Bax and Bcl\u20102), and synaptic plasticity\u2010related genes (brain\u2010derived neurotrophic factor [BDNF] and PSD\u201095) in the hippocampus were analyzed by quantitative real\u2010time PCR. Hematoxylin and eosin staining were used to observe the morphology of neurons in the hippocampal DG subregions. Western blot was performed to detect the protein expression levels of BDNF, PSD\u201095, Bax, Bcl\u20102, PI3K, p\u2010PI3K, AKT, p\u2010AKT, GSK\u20103\u03b2, p\u2010GSK\u20103\u03b2 in the hippocampus. MK\u2010SI neurodevelopmental disease model studies have shown that compared with sham group, MK\u2010SI group exhibit higher levels of autonomic activity, stereotyped behaviors, withdrawal from social interactions, dysregulated sensorimotor gating, and impaired recognition and spatial memory. These findings imply that the MK\u2010SI model can mimic symptoms similar to those of SZ. Compared with the MK\u2010SI model, high doses of SEP\u2010856 all significantly reduced increased activity, improved social interaction, reduced stereotyping behavior, reversed sensorimotor gating dysregulation, and improved recognition memory and spatial memory impairment in MK\u2010SI mice. In addition, SEP\u2010856 can reduce the release of proinflammatory factors in the MK\u2010SI model, promote the expression of BDNF and PSD\u201095 in the hippocampus, correct the Bax\/Bcl\u20102 imbalance, turn on the PI3K\/AKT\/GSK\u20103\u03b2 signaling pathway, and ultimately help the MK\u2010SI mice's behavioral abnormalities. SEP\u2010856 may play an antipsychotic role in MK\u2010SI \u201cdual\u2010hit\u201d model\u2010induced SZ\u2010like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro\u2010inflammatory substances in the hippocampal region, and subsequently initiating the PI3K\/AKT\/GSK\u20103\u03b2 signaling cascade.\n                  <\/jats:p>","DOI":"10.1002\/ddr.22225","type":"journal-article","created":{"date-parts":[[2024,6,16]],"date-time":"2024-06-16T03:45:00Z","timestamp":1718509500000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["SEP\u2010363856 exerts neuroprotection through the PI3K\/AKT\/GSK\u20103\u03b2 signaling pathway in a dual\u2010hit neurodevelopmental model of schizophrenia\u2010like mice"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-4866","authenticated-orcid":false,"given":"Mengdie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Psychiatry Chaohu Hospital of Anhui Medical University Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Mental Health and Psychological Sciences Anhui Medical University Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Chaohu Hospital of Anhui Medical University Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Chaohu Hospital of Anhui Medical University Hefei Anhui 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