title: Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: relevance for mental disorders.
abstract: Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood. GluA1-containing AMPA receptors, which are located predominantly on hippocampal neurons, are the primary molecular determinants of synaptic plasticity. We investigated here the consequences of the inducible deletion of GluA1 AMPA receptors in glutamatergic neurons during late adolescence. We generated mutant mice with a tamoxifen-inducible deletion of GluA1 under the control of the CamKII promoter for temporally and spatially restricted gene manipulation. GluA1 ablation during late adolescence induced cognitive impairments, but also marked hyperlocomotion and sensorimotor gating deficits. Unlike the global genetic deletion of GluA1, inducible GluA1 ablation during late adolescence resulted in normal sociability. Deletion of GluA1 induced redistribution of GluA2 subunits, suggesting AMPA receptor trafficking deficits. Mutant animals showed increased hippocampal NMDA receptor expression and no change in striatal dopamine concentration. Our data provide new insight into the role of deficient AMPA receptors specifically during late adolescence in inducing several cognitive and behavioral alterations with possible relevance for neuropsychiatric disorders.
authors: Department of Psychiatry and Psychotherapy, RG Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
authors: Dragos
authors: D
authors: Inta
authors: Miriam A
authors: MA
authors: Vogt
authors: Hasan
authors: H
authors: Elkin
authors: Tillmann
authors: T
authors: Weber
authors: Juan M
authors: JM
authors: Lima-Ojeda
authors: Miriam
authors: M
authors: Schneider
authors: Alessia
authors: A
authors: Luoni
authors: Marco A
authors: MA
authors: Riva
authors: Karen
authors: K
authors: Gertz
authors: Julian
authors: J
authors: Hellmann-Regen
authors: Golo
authors: G
authors: Kronenberg
authors: Andreas
authors: A
authors: Meyer-Lindenberg
authors: Rolf
authors: R
authors: Sprengel
authors: Peter
authors: P
authors: Gass
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism*; D003342:Corpus Striatum / Q000254:growth & development / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term; D001523:Mental Disorders; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D055139:Sensory Gating / Q000502:physiology; D012919:Social Behavior
chemical_list: D004298:Dopamine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2
keywords: GluA2; cognitive dysfunction; excitatory neurons; neuropsychiatric disorders; pharmacogenetics