Altered AMPA receptor subunit configuration contributes to dysfunctional excitatory synaptic activity in BCNU rat-model of focal cortical dysplasia (FCD).

Abstract

Focal Cortical Dysplasia (FCD) is a leading cause of drug-resistant epilepsy, yet its molecular drivers remain unclear. AMPA receptor subunit composition plays a key role in synaptic excitability and may be altered in FCD. To investigate whether dysregulated expression of AMPAR subunits, specifically GluA1 and GluA4, contributes to the enhanced excitatory synaptic activity in FCD rat-model, BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) was administered in-utero to induce FCD in rats. At postnatal-day 30 (P30), somatosensory cortex samples were analysed using qPCR and immunohistochemistry for GluA1, GluA4, and GluN2B. Whole-cell patch clamp recordings of spontaneous excitatory postsynaptic currents (sEPSCs) were performed, with APV and CNQX used for pharmacological dissection. GluA1 expression was significantly reduced in FCD tissue at both mRNA and protein levels (p&#xa0;<&#xa0;0.05), while GluA4 showed significant upregulation (p&#xa0;<&#xa0;0.01). GluN2B levels remained unchanged. Functionally, FCD neurons displayed increased sEPSC amplitude (p&#xa0;=&#xa0;0.0022) and frequency (p&#xa0;=&#xa0;0.045), with a leftward shift in interevent intervals (p&#xa0;=&#xa0;0.0002). Power spectrum analysis further supported a distinct glutamatergic signature and increased channel activity in FCD. A near-suppression of events after CNQX&#xa0;+&#xa0;APV application confirmed the glutamatergic nature of currents. Significant reduction of sEPSC amplitude and increase in rise-time in control group on APV application with no change in FCD group suggests AMPA receptor predominance in excitatory synaptic activity in FCD. Our findings reveal alterations in subunit configuration of AMPARs in FCD, driving hyperexcitable synaptic transmission through faster, less desensitizing glutamatergic currents. These molecular and functional changes suggest pathological reprogramming of excitatory synapses in FCD and AMPARs as potential therapeutic targets.