title: APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures.
abstract: 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 β-catenin pathways. However, evidence linking malfunction of β-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 β-catenin, leads to excessive β-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/β-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.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pirone
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States; Neuroscience Program, Tufts Sackler School of Biomedical Sciences, Boston, MA 02111, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States; Neuroscience Program, Tufts Sackler School of Biomedical Sciences, Boston, MA 02111, United States.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Lau
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hampton
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zayachkivsky
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Yee
authors.affiliation: VA Eastern Colorado Health System, Golden, CO 80401, United States.
authors.forename: Audrey
authors.initials: A
authors.lastname: Yee
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States. Electronic address: Michele.Jacob@Tufts.edu.
authors.forename: Michele H
authors.initials: MH
authors.lastname: Jacob
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States. Electronic address: Chris.Dulla@Tufts.edu.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Dulla
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018345:Mice, Knockout; D009068:Movement / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013036:Spasms, Infantile / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; C000613192:adenomatous polyposis coli protein, mouse; D051176:beta Catenin
keywords: Cortex; Epilepsy; Infantile spasms; Wnt signaling; β-Catenin