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The Journal of Neuroscience, February 18, 2009, 29(7):2238-2251; doi:10.1523/JNEUROSCI.5851-08.2009

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Cellular/Molecular
Restricted Cortical and Amygdaloid Removal of Vesicular Glutamate Transporter 2 in Preadolescent Mice Impacts Dopaminergic Activity and Neuronal Circuitry of Higher Brain Function

Åsa Wallén-Mackenzie,¹ Karin Nordenankar,¹ Kim Fejgin,^4 * Malin C. Lagerström,^1 * Lina Emilsson,¹ Robert Fredriksson,¹ Caroline Wass,⁴ Daniel Andersson,⁴ Emil Egecioglu,⁵ My Andersson,⁵ Joakim Strandberg,⁵ Örjan Lindhe,⁶ Helgi B. Schiöth,¹ Karima Chergui,⁷ Eric Hanse,⁵ Bengt Långström,² Anders Fredriksson,¹ Lennart Svensson,⁴ Erika Roman,³ and Klas Kullander¹

Departments of ¹Neuroscience, ²Biochemistry and Organic Chemistry, and ³Pharmaceutical Biosciences, Uppsala University, 751 24 Uppsala, Sweden, ⁴Departments of Pharmacology and ⁵Physiology, Göteborg University, 405 30 Göteborg, Sweden, ⁶Uppsala Imanet, GE Healthcare, 751 09 Uppsala, Sweden, and ⁷Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden

Correspondence should be addressed to Klas Kullander, Department of Neuroscience, Uppsala University, Box 593, 75124 Uppsala, Sweden. Email: klas.kullander{at}neuro.uu.se

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.

Key words: neuronal network; physiology; CNS; transmitter; behavior; schizophrenia

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Received Dec. 9, 2008; accepted Jan. 7, 2009.

Correspondence should be addressed to Klas Kullander, Department of Neuroscience, Uppsala University, Box 593, 75124 Uppsala, Sweden. Email: klas.kullander{at}neuro.uu.se

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