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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function

Wallén-Mackenzie, Asa; Nordenankar, Karin; Fejgin, Kim; Lagerström, Malin C; Emilsson, Lina; Fredriksson, Robert; Wass, Caroline; Andersson, Daniel LU ; Egecioglu, Emil LU and Andersson, My LU , et al. (2009) In The Journal of neuroscience : the official journal of the Society for Neuroscience 29(7). p.51-2238
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... (More)

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.

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@article{03f364f6-24f5-48f9-9db2-2ab13814878b,
  abstract     = {<p>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.</p>},
  author       = {Wallén-Mackenzie, Asa and Nordenankar, Karin and Fejgin, Kim and Lagerström, Malin C and Emilsson, Lina and Fredriksson, Robert and Wass, Caroline and Andersson, Daniel and Egecioglu, Emil and Andersson, My and Strandberg, Joakim and Lindhe, Orjan and Schiöth, Helgi B. and Chergui, Karima and Hanse, Eric and Långström, Bengt and Fredriksson, Anders and Svensson, Lennart and Roman, Erika and Kullander, Klas},
  issn         = {1529-2401},
  keyword      = {Aging,Amygdala,Animals,Antipsychotic Agents,Behavior, Animal,Cell Differentiation,Cerebral Cortex,Corpus Striatum,Dopamine,Glutamic Acid,Hippocampus,Male,Mice,Mice, Knockout,Neural Pathways,Neuronal Plasticity,Nucleus Accumbens,Schizophrenia,Sensory Gating,Synaptic Transmission,Vesicular Glutamate Transport Protein 2,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {02},
  number       = {7},
  pages        = {51--2238},
  publisher    = {Society for Neuroscience},
  series       = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
  title        = {Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.5851-08.2009},
  volume       = {29},
  year         = {2009},
}