Modelling etiopathogenesis of the FOXG1-duplication-linked variant of West syndrome

ABSTRACT Here we describe the characterization of a novel Foxg1-GOF model we created to dissect the role of Foxg1 in postmitotic neuronal differentiation and reconstruct pathogenetic mechanisms which underlie the FOXG1 duplication-linked West syndrome. This is a devastating neurological disorder, triggered by a complex variety of pathogenic conditions. It is characterized by infantile spasms, abnormal EEG with hypsarrhytmia and seizures and dramatic cognitive impairment. For it only symptomatic treatments are presently available. As expected, these Foxg1-GOF mice showed increased neuronal activity in baseline conditions and were more prone to limbic motor seizures upon kainic acid administration. A preliminary developmental profiling of their cerebral cortex unveiled four major histogenetic anomalies, likely contributing to their hyperexcitability. These anomalies were: (1) an altered neocortical laminar blueprint with impaired layer VI/layer V segregation and defective activation of layer IV-II programs; (2) a substantial reduction of PV+ interneurons; (3) a patterned, area- and lamina-specific astrocyte deprivation; (4) a defective expression of the Gabra1 receptor subunit. Similar phenomena might concur to neurological anomalies of West syndrome patients harboring FOXG1 duplications. A parallel in vitro study, run on dissociated cortico-cerebral cultures, revealed that a substantial Foxg1 upregulation occurred upon delivery of depolarizing stimuli. Neuronal, activity-linked Foxg1 elevation required the presence of astrocytes. Activity-linked Foxg1 fluctuations were inter-twinned with immediate-early genes fluctuations and depended on them, according to distinct, neuron- and astrocyte-specific patterns. In West syndrome patients with augmented FOXG1 dosage, a FOXG1-mRNA increase evoked by depolarizing stimuli might ignite a vicious circle, exacerbating neuronal hyperactivity and contributing to interictal EEG anomalies and seizures.