| First Author | Pirone A | Year | 2017 |
| Journal | Neurobiol Dis | Volume | 98 |
| Pages | 149-157 | PubMed ID | 27852007 |
| Mgi Jnum | J:259632 | Mgi Id | MGI:6141954 |
| Doi | 10.1016/j.nbd.2016.11.002 | Citation | Pirone A, et al. (2017) APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal beta-catenin levels, neonatal spasms, and chronic seizures. Neurobiol Dis 98:149-157 |
| abstractText | Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter beta-catenin pathways. However, evidence linking malfunction of beta-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of beta-catenin, leads to excessive beta-catenin levels and multiple salient features of human IS. Compared with wild-type littermates, neonatal APC cKO mice exhibit flexion-extension motor spasms and abnormal high-amplitude electroencephalographic discharges. Additionally, the frequency of excitatory postsynaptic currents is increased in layer V pyramidal cells, the major output neurons of the cerebral cortex. At adult ages, APC cKOs display spontaneous electroclinical seizures. These data provide the first evidence that malfunctions of APC/beta-catenin pathways cause pathophysiological changes consistent with IS. Our findings demonstrate that the APC cKO is a new genetic model of IS, provide novel insights into molecular and functional alterations that can lead to IS, and suggest novel targets for therapeutic intervention. |
