Cortical Seizures in FoxG1+/- Mice are Accompanied by Akt/S6 Overactivation, Excitation/Inhibition Imbalance and Impaired Synaptic Transmission.

Giovanna Testa,Antonino Cattaneo,Laura Pancrazi,Francesco Olimpico,Marco Mainardi,Ugo Borello,Matteo Caleo,Mario Costa

doi:10.3390/ijms20174127

Abstract

The correct morphofunctional shaping of the cerebral cortex requires a continuous interaction between intrinsic (genes/molecules expressed within the tissue) and extrinsic (e.g., neural activity) factors at all developmental stages. Forkhead Box G1 (FOXG1) is an evolutionarily conserved transcription factor, essential for the cerebral cortex patterning and layering. FOXG1-related disorders, including the congenital form of Rett syndrome, can be caused by deletions, intragenic mutations or duplications. These genetic alterations are associated with a complex phenotypic spectrum, spanning from intellectual disability, microcephaly, to autistic features, and epilepsy. We investigated the functional correlates of dysregulated gene expression by performing electrophysiological assays on FoxG1+/− mice. Local Field Potential (LFP) recordings on freely moving animals detected cortical hyperexcitability. On the other hand, patch-clamp recordings showed a downregulation of spontaneous glutamatergic transmission. These findings were accompanied by overactivation of Akt/S6 signaling. Furthermore, the expression of vesicular glutamate transporter 2 (vGluT2) was increased, whereas the level of the potassium/chloride cotransporter KCC2 was reduced, thus indicating a higher excitation/inhibition ratio. Our findings provide evidence that altered expression of a key gene for cortical development can result in specific alterations in neural circuit function at the macro- and micro-scale, along with dysregulated intracellular signaling and expression of proteins controlling circuit excitability.

Highlights

The complexity of the mature six-layered structure of the mammalian cerebral cortex is achieved through a long and precisely regulated developmental process controlling neurogenesis, neuronal migration and differentiation
Based on our previous findings showing higher propensity to proconvulsant-induced generalized seizures [11]), we assessed the electrophysiological profile of the primary motor cortex (M1) of freely moving FoxG1+/− mice, using chronic implants for local field potential (LFP) recordings (Figure 1A)
Mutations in FoxG1 have been recently recognized as causing non-X-linked Rett syndrome [7,14]

Summary

Introduction

The complexity of the mature six-layered structure of the mammalian cerebral cortex is achieved through a long and precisely regulated developmental process controlling neurogenesis, neuronal migration and differentiation. Cortical abnormalities caused by altered expression of genes regulating brain development at different levels, e.g., gene transcription [1] or cell migration [2], constitute a significant fraction of pediatric pathologies associated to intellectual disability [3]. Heterozygous mutations in FOXG1 are compatible with life, but result in reduced size of cerebral hemispheres, alterations in cortical layering [6] and severe intellectual disability with autism spectrum disorder (ASD)-like features [7]. In comparison to “classical” RTT due to MECP2 mutations, FoxG1-associated variants share ASD signs, and tend to show an earlier onset, a higher occurrence of epileptic seizures, and callosal abnormalities [9]. The localization of FoxG1 on the 14q12 chromosomal region allows the mutation to cause the pathology in both sexes, in contrast to X-linked RTT caused by MECP2 mutations [7]

Methods

Results

Conclusion