Focal Cortical Dysplasia (FCD) is a developmental disorder of the cerebral cortex characterized by cortical dyslamination and intractable seizures (Kabat and Król, 2012). FCD exhibits features of typical immature brains, including clusters of immature neurons, dysmorphic neurons, cytomegalic neurons, and balloon cells (Blümcke et al., 2011). Interictal discharges and pathological high-frequency oscillations (HFOs) in FCD are associated with increased GABAergic activity (Blauwblomme et al., 2019; Cepeda et al., 2020). Changes in interneuron density, GABA neurotransmitter levels, and GABAA receptor expression have been shown to contribute to alterations in GABAA receptor-mediated activity in FCD (Calcagnotto et al., 2005; Gong et al., 2021; Sharma et al., 2021).

Clinically, the age at seizure onset in FCD patients ranges from 0 to 60 years, with most of the patients experiencing early onset, typically before 5 years of age (Fauser et al., 2006; Siegel et al., 2005). Notably, early-onset FCD patients (type II) exhibit cytoarchitectural abnormalities, whereas those with late-onset FCD (type IA) only show architectural abnormalities (Fauser et al., 2006; Tassi et al., 2002). We have previously reported that GABAA receptor associated synaptic activity varies with the age at seizure onset and contributes to development of differential epileptogenicity in early-onset and late-onset patients with FCD type I and II (Banerjee et al., 2020). These findings underscore the existence of differential neural networks in FCD patients with respect to the age at seizure onset. Thus, it is imperative to understand age-dependent changes in GABAA receptor-mediated synaptic activity during brain development associated with different neural networks in FCD patients.

Altered configuration of GABAA receptor subunits could contribute to development of abnormal neural networks in FCD. The expression of GABAA receptors containing the α4 subunit is reported to be higher in the focal lesions of FCD patients (Sharma et al., 2021; Jansen et al., 2010). Another study showed that the expression of α1 subunit was significantly reduced in resected specimens from FCD type IIA patients (Talos et al., 2012). Cell type-specific expression studies showed reduced expression of α1 and α2 subunits of GABAA receptors in dysplastic and heterotopic neurons in FCD (Crino et al., 2001). The configurational changes in GABAA receptors may alter receptor kinetics, disrupting GABAergic activity and potentially leading to hyperexcitability (Sallard et al., 2021). However, the role of altered GABAA receptor configuration in the generation of epileptogenic networks in age-dependent manner in FCD is still not clear.

In this study, we examined whether GABAA receptor subunit configuration and function alter in an age-dependent manner in FCD. To address this, we utilized the BCNU rat model of FCD, which closely resembles human FCD type IIA. This model exhibits cortical dyslamination, the presence of dysmorphic neurons and spontaneous epileptiform discharges (Moroni et al., 2008; Moroni et al., 2011a; Moroni et al., 2011b; Inverardi et al., 2013; Aquiles et al., 2023; Pennacchio et al., 2015). We assessed possible alterations in the neurotransmitter levels and configuration of GABAA receptors due to changes in expression of GABAA receptor α subunits in an age dependent manner. Further, we analyzed the effect of configuration changes in GABAA receptor on the GABAA receptor-mediated synaptic activity in different age groups of FCD rats.