title: Developmental Inhibition of Gsk3 Rescues Behavioral and Neurophysiological Deficits in a Mouse Model of Schizophrenia Predisposition.
abstract: While the genetic basis of schizophrenia is increasingly well characterized, novel treatments will require establishing mechanistic relationships between specific risk genes and core phenotypes. Rare, highly penetrant risk genes such as the 22q11.2 microdeletion are promising in this regard. Df(16)A(+/-) mice, which carry a homologous microdeletion, have deficits in hippocampal-prefrontal connectivity that correlate with deficits in spatial working memory. These mice also have deficits in axonal development that are accompanied by dysregulated Gsk3β signaling and can be rescued by Gsk3 antagonists. Here we show that developmental inhibition of Gsk3 rescues deficits in hippocampal-prefrontal connectivity, task-related neural activity, and spatial working memory behavior in Df(16)A(+/-) mice. Taken together, these results provide mechanistic insight into how the microdeletion results in cognitive deficits, and they suggest possible targets for novel therapies.
authors.affiliation: Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA; Pharmacology Research Laboratories I, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA; Department of Neuroscience, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Mukai
authors.affiliation: Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA; Division of Integrative Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032, USA. Electronic address: jg343@cumc.columbia.edu.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Gordon
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA; Department of Neuroscience, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. Electronic address: jag90@cumc.columbia.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004062:DiGeorge Syndrome / Q000150:complications / Q000235:genetics; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D001523:Mental Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009422:Nervous System Diseases / Q000209:etiology*; D012559:Schizophrenia / Q000150:complications* / Q000235:genetics / Q000473:pathology; D013826:Theta Rhythm / Q000235:genetics
chemical_list: D038362:Glycogen Synthase Kinase 3