Format

Send to

Choose Destination
Eur J Neurosci. 2014 Jul;40(1):2255-63. doi: 10.1111/ejn.12594. Epub 2014 Apr 23.

Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling.

Author information

1
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

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 D2 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.

KEYWORDS:

14-3-3; NMDA; burst firing; mouse; schizophrenia

PMID:
24754704
PMCID:
PMC4331169
DOI:
10.1111/ejn.12594
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center