title: Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area.
abstract: There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.
authors: Institute of Neurophysiology, Goethe University, Frankfurt 60590, Germany;
authors: Sabine
authors: S
authors: Krabbe
authors: Institute of Applied Physiology, University of Ulm, Ulm 89081, Germany;
authors: Johanna
authors: J
authors: Duda
authors: Institute of Neurophysiology, Goethe University, Frankfurt 60590, Germany;
authors: Julia
authors: J
authors: Schiemann
authors: Institute of Applied Physiology, University of Ulm, Ulm 89081, Germany;
authors: Christina
authors: C
authors: Poetschke
authors: Institute of Mathematics, Goethe University, Frankfurt 60325, Germany;
authors: Gaby
authors: G
authors: Schneider
authors: Departments of Psychiatry and New York State Psychiatric Institute, New York, NY 10032 Neuroscience, Howard Hughes Medical Institute, and Kavli Institute for Brain Science, Columbia University, New York, NY 10032; and erk5@columbia.edu es534@columbia.edu.
authors: Eric R
authors: ER
authors: Kandel
authors: Institute of Applied Physiology, University of Ulm, Ulm 89081, Germany;
authors: Birgit
authors: B
authors: Liss
authors: Institute of Neurophysiology, Goethe University, Frankfurt 60590, Germany;
authors: Jochen
authors: J
authors: Roeper
authors: Departments of Psychiatry and New York State Psychiatric Institute, New York, NY 10032 erk5@columbia.edu es534@columbia.edu.
authors: Eleanor H
authors: EH
authors: Simpson
mesh_terms: D000818:Animals; D003072:Cognition Disorders; D003342:Corpus Striatum / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004594:Electrophysiology; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D016011:Normal Distribution; D010641:Phenotype; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D009435:Synaptic Transmission; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D017448:Receptors, Dopamine D2
keywords: NMDA receptor; burst activity; dopamine D2 receptor; schizophrenia; ventral tegmental area