title: Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia.
abstract: Homer proteins are involved in the functional assembly of postsynaptic density proteins at glutamatergic synapses and are implicated in learning, memory and drug addiction. Here, we report that Homer1-knockout (Homer1-KO) mice exhibit behavioral and neurochemical abnormalities that are consistent with the animal models of schizophrenia. Relative to wild-type mice, Homer1-KO mice exhibited deficits in radial arm maze performance, impaired prepulse inhibition, enhanced 'behavioral despair', increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior. No-net-flux in vivo microdialysis revealed a decrease in extracellular glutamate content in the nucleus accumbens and an increase in the prefrontal cortex. Moreover, in Homer1-KO mice, cocaine did not stimulate a rise in frontal cortex extracellular glutamate levels, suggesting hypofrontality. These behavioral and neurochemical data derived from Homer1 mutant mice are consistent with the recent association of schizophrenia with a single-nucleotide polymorphism in the Homer1 gene and suggest that the regulation of extracellular levels of glutamate within limbo-corticostriatal structures by Homer1 gene products may be involved in the pathogenesis of this neuropsychiatric disorder.
authors: Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC, USA. szumlink@musc.edu
authors: K K
authors: KK
authors: Szumlinski
authors: K D
authors: KD
authors: Lominac
authors: M J
authors: MJ
authors: Kleschen
authors: E B
authors: EB
authors: Oleson
authors: M H
authors: MH
authors: Dehoff
authors: M K
authors: MK
authors: Schwarz
authors: M K
authors: MK
authors: Schwartz
authors: P H
authors: PH
authors: Seeburg
authors: P H
authors: PH
authors: Seeberg
authors: P F
authors: PF
authors: Worley
authors: P W
authors: PW
authors: Kalivas
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003216:Conditioning, Operant / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D017353:Gene Deletion; D018698:Glutamic Acid / Q000378:metabolism*; D000072233:Homer Scaffolding Proteins; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology; D009714:Nucleus Accumbens / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D018698:Glutamic Acid