title: Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
abstract: A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
authors.affiliation: Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden.
authors.forename: Asa
authors.initials: A
authors.lastname: Wallén-Mackenzie
authors.forename: Karin
authors.initials: K
authors.lastname: Nordenankar
authors.forename: Kim
authors.initials: K
authors.lastname: Fejgin
authors.forename: Malin C
authors.initials: MC
authors.lastname: Lagerström
authors.forename: Lina
authors.initials: L
authors.lastname: Emilsson
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.forename: Caroline
authors.initials: C
authors.lastname: Wass
authors.forename: Daniel
authors.initials: D
authors.lastname: Andersson
authors.forename: Emil
authors.initials: E
authors.lastname: Egecioglu
authors.forename: My
authors.initials: M
authors.lastname: Andersson
authors.forename: Joakim
authors.initials: J
authors.lastname: Strandberg
authors.forename: Orjan
authors.initials: O
authors.lastname: Lindhe
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Karima
authors.initials: K
authors.lastname: Chergui
authors.forename: Eric
authors.initials: E
authors.lastname: Hanse
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Anders
authors.initials: A
authors.lastname: Fredriksson
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
authors.forename: Erika
authors.initials: E
authors.lastname: Roman
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
mesh_terms: D000375:Aging / Q000378:metabolism; D000679:Amygdala / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology*; D003342:Corpus Striatum / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000235:genetics; D009714:Nucleus Accumbens / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D055139:Sensory Gating / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D004298:Dopamine