Foxg1 Upregulation Enhances Neocortical Activity

Abstract

Foxg1 is an ancient transcription factor gene orchestrating a number of neurodevelopmental processes taking place in the rostral brain. In this study, we investigated its impact on neocortical activity. We found that mice overexpressing Foxg1 in neocortical pyramidal cells displayed an electroencephalography (EEG) with increased spike frequency and were more prone to kainic acid (KA)-induced seizures. Consistently, primary cultures of neocortical neurons gain-of-function for Foxg1 were hyperactive and hypersynchronized. That reflected an unbalanced expression of key genes encoding for ion channels, gamma aminobutyric acid and glutamate receptors, and was likely exacerbated by a pronounced interneuron depletion. We also detected a transient Foxg1 upregulation ignited in turn by neuronal activity and mediated by immediate early genes. Based on this, we propose that even small changes of Foxg1 levels may result in a profound impact on pyramidal cell activity, an issue relevant to neuronal physiology and neurological aberrancies associated to FOXG1 copy number variations.

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

“…Mecp2 overexpression in these models led to electrographic discharges accompanied by behavioral seizures in mice [ 209 , 211 ]. Foxg1 overexpression in mice deep-layer neocortical projection neurons also led to higher neuronal excitability assessed by frequency of electrographic high-amplitude spikes and severity of behavioral seizures induced by kainic acid [ 212 ].…”

Diverse inflammatory threats modulate astrocytes Ca2+ signaling via connexin43 hemichannels in organotypic spinal slices

“…The lentiviruses were generated and titrated as previously described [ 62 ]. Lentiviral vectors employed in this study include: LV_pGfap-rtTA2S-M2, (built as previously shown [ 63 ]) and LV_TREt-mCherry, kindly provided by professor Antonello Mallamaci's lab. The slices were infected with 5 µL of lentiviral preparation, whose titres were 4 × 106 and 1 × 107 respectively.…”

Multidimensional Functional Profiling of Human Neuropathogenic FOXG1 Alleles in Primary Cultures of Murine Pallial Precursors

“…Shut down to allow neuronogenic precursors exit from cell cycle, Foxg1 is normally reactivated in newborn murine neurons [8], where it is needed to finely tune layer identity [9,10], dendritic architecture [5,11,12] as well as activity and excitability [14]. All that offers further valuable opportunities to functionally score mutant FOXG1 alleles against their wild type counterparts.…”

“…It biases neocortical neurons to specific layer identities [7][8][9][10] and promotes their morphological maturation [5,[11][12][13]. Moreover, it sustains activity and excitability of these neurons [13,14], being in turn upregulated by neuronal activity [14,15]. As a consequence of that, experimental Foxg1 manipulation in mouse models results in prominent, cognitive and behavioral, phenotypes.…”