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The prefrontal cortex (PFC) is particularly vulnerable to the factors that affect neuronal and synaptic development, with abnormal PFC development leading to increased epilepsy susceptibility. This study used 8\u2010OH\u2010DPAT to activate PFC 5\u2010HT1A to investigate its role in attenuating epileptic susceptibility in a valproic acid (VPA)\u2010induced rat model of ASD and potential mechanisms involving Kir3 channel\u2010mediated hyperpolarization. Rats were prenatally exposed to VPA to induce autism\u2010like behaviors, and successful induction was verified through behavioral, morphological, and electrophysiological assessments. Neuronal loss, dendritic complexity, and spine density in the PFC were evaluated using Nissl and Golgi staining. Pentylenetetrazol (PTZ) was used to induce chemical kindling for assessing seizure susceptibility in the ASD model. Spontaneous action potential (sAP) and miniature excitatory postsynaptic current (mEPSC) frequencies were electrophysiologically recorded. The selective 5\u2010HT1A receptor (5\u2010HT1AR) agonist 8\u2010OH\u2010DPAT was used to investigate its anticonvulsant effects. ASD rats exhibited significant neuronal loss, reduced dendritic complexity, and lower dendritic spine density in the PFC. The PTZ\u2010treated ASD group showed reduced seizure onset latency, prolonged stage IV seizure duration, and higher seizure incidence, indicating increased susceptibility to epilepsy. Untreated rats displayed reduced sAP and mEPSC frequencies in PFC pyramidal neurons, suggesting E\/I imbalance. However, PTZ treatment increased sAP and mEPSC frequencies, reflecting enhanced neuronal excitability. Treatment with 8\u2010OH\u2010DPAT significantly delayed seizure onset, shortened seizure duration, and reduced seizure incidence. Furthermore, 8\u2010OH\u2010DPAT decreased sAP and mEPSC frequencies. These effects were attenuated after applying tertiapin\u2010Q (TQ), underscoring the role of inwardly rectifying potassium (Kir3) channels in mediating 8\u2010OH\u2010DPAT\u2010induced anticonvulsant effects. In conclusion, PFC 5\u2010HT1AR activity alleviated epileptic activity through Kir3 channel\u2010mediated hyperpolarization. These findings highlight 5\u2010HT1ARs and Kir3 channels as promising therapeutic targets for epilepsy associated with ASD.<\/jats:p>","DOI":"10.1155\/np\/4005949","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T11:06:07Z","timestamp":1777979167000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prefrontal Cortex 5\u2010HT1A Receptor\u2010Coupled Inwardly Rectifying Potassium Channels Decreased Seizure Susceptibility in Rat Models With Autism Spectrum 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