Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Sabine Krabbe, Johanna Duda, Julia Schiemann, Christina Poetschke, Gaby Schneider, Eric R. Kandel, Birgit Liss, Jochen Roeper, and Eleanor H. Simpson
PNAS published ahead of print February 9, 2015 https://doi.org/10.1073/pnas.1500450112

  1. Contributed by Eric R. Kandel, January 16, 2015 (sent for review December 17, 2014; reviewed by Ann M. Graybiel and Patricio O’Donnell)

Significance

Patients with schizophrenia suffer from cognitive and negative deficits that are largely resistant to current therapeutic strategies. Here, using a genetic mouse model that displays phenotypes similar to these cognitive and negative symptoms, we found that increased postsynaptic D2 receptor (D2R) activity in the striatum leads to changes in the firing pattern of presynaptic dopamine (DA) neurons of the midbrain. These alterations occur in the ventral tegmental area (VTA) of the midbrain, but not in the substantia nigra, suggesting that DA pathways may be differently regulated by striatal D2R hyperactivity. The changes in neuron firing patterns were accompanied by a reduction in NMDA receptor subunits selectively in dopaminergic VTA neurons, providing a potential new target for the treatment of schizophrenia symptoms.

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.

Footnotes

  • ↵1Present address: Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.

  • ↵2Present address: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.

  • ↵3To whom correspondence may be addressed. Email: erk5{at}columbia.edu or es534{at}columbia.edu.

  • ↵4J.R. and E.H.S. contributed equally to this work.

  • Author contributions: S.K., E.R.K., B.L., J.R., and E.H.S. designed research; S.K., J.D., J.S., and C.P. performed research; S.K., J.S., and G.S. analyzed data; and S.K., E.R.K., B.L., J.R., and E.H.S. wrote the paper.

  • Reviewers: A.M.G., Massachusetts Institute of Technology; and P.O., Pfizer, Inc.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1500450112/-/DCSupplemental.

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Striatal D2 receptors and dopamine cell activity
Sabine Krabbe, Johanna Duda, Julia Schiemann, Christina Poetschke, Gaby Schneider, Eric R. Kandel, Birgit Liss, Jochen Roeper, Eleanor H. Simpson
Proceedings of the National Academy of Sciences Feb 2015, 201500450; DOI: 10.1073/pnas.1500450112
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