Publication Date
5-24-2022
Journal
Brain
DOI
10.1093/brain/awab390
PMID
34849602
PMCID
PMC9128821
PubMedCentral® Posted Date
11-25-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adaptor Proteins, Signal Transducing, Animals, Brain, Cell Cycle Proteins, Epilepsy, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Mice, Neurons, Phosphorylation, Seizures, TOR Serine-Threonine Kinases, malformation of cortical development, seizures, cap-dependent translation, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, in utero electroporation
Abstract
Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.