Prefrontal Cortex 5‐HT1A Receptor‐Coupled Inwardly Rectifying Potassium Channels Decreased Seizure Susceptibility in Rat Models With Autism Spectrum Disorder

Dysregulation of serotonin 1A receptor (5-HT1A), a G protein-coupled inhibitory receptor, is implicated in the pathogenesis of both autism spectrum disorder (ASD) and epilepsy. 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-OH-DPAT to activate PFC 5-HT1A to investigate its role in attenuating epileptic susceptibility in a valproic acid (VPA)-induced rat model of ASD and potential mechanisms involving Kir3 channel-mediated hyperpolarization. Rats were prenatally exposed to VPA to induce autism-like 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-HT1A receptor (5-HT1AR) agonist 8-OH-DPAT 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-treated 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-OH-DPAT significantly delayed seizure onset, shortened seizure duration, and reduced seizure incidence. Furthermore, 8-OH-DPAT decreased sAP and mEPSC frequencies. These effects were attenuated after applying tertiapin-Q (TQ), underscoring the role of inwardly rectifying potassium (Kir3) channels in mediating 8-OH-DPAT-induced anticonvulsant effects. In conclusion, PFC 5-HT1AR activity alleviated epileptic activity through Kir3 channel-mediated hyperpolarization. These findings highlight 5-HT1ARs and Kir3 channels as promising therapeutic targets for epilepsy associated with ASD.