[P2-100] Selective loss of Pten in the hippocampal dentate gyrus causes age-dependent seizures in mice
[Background] Epilepsy is a frequent comorbidity (30 - 40%) in patients with autism spectrum disorder (ASD). Recent studies utilizing massive sequencing data identified hundreds of genes that were associated with epilepsy and ASD. Among them, AKT and mammalian target of rapamycin (mTOR)-related signals have been recently implicated in the pathogenic processes of both epilepsy and ASD. To clarify the functional roles of the AKT-mTOR pathway in the postnatal neural circuit formation, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in proopiomelanocortin-expressing neurons of the hippocampal dentate gyrus.
[Results] The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus with unbalanced expressions of excitatory postsynaptic and inhibitory neuron makers at 6-8 weeks. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the onset of seizures and reversed these molecular phenotypes.
[Conclusion] These data indicate that the AKT-mTOR pathway regulates hippocampal excitability in the postnatal brain.
[Results] The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus with unbalanced expressions of excitatory postsynaptic and inhibitory neuron makers at 6-8 weeks. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the onset of seizures and reversed these molecular phenotypes.
[Conclusion] These data indicate that the AKT-mTOR pathway regulates hippocampal excitability in the postnatal brain.