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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Sustained N-methyl-D-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling
The European journal of neuroscience, v 40(1), pp 2255-2263
23 Apr 2014
PMID: 24754704
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Chronic
N
-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e. tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D
2
autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high-frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing.
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Details
- Title
- Sustained N-methyl-D-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling
- Creators
- Mark J. Ferris - Wake Forest UniversityMarija Milenkovic - University of TorontoShuai Liu - Italian Institute of TechnologyCatharine A. Mielnik - University of TorontoPieter Beerepoot - University of TorontoCarrie E. John - Wake Forest UniversityRodrigo A. España - Wake Forest UniversityTatyana D. Sotnikova - Italian Institute of TechnologyRaul R. Gainetdinov - Italian Institute of TechnologyStephanie L. Borgland - Department of Anesthesiology, Pharmacology & Therapeutics, University of British Colombia, Vancouver, BC, CanadaSara R. Jones - Wake Forest UniversityAmy J. Ramsey - University of Toronto
- Publication Details
- The European journal of neuroscience, v 40(1), pp 2255-2263
- Publisher
- Wiley
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000339257400009
- Scopus ID
- 2-s2.0-84903886170
- Other Identifier
- 991019292221104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences