SustainedN-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling

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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.

Dopamine neurons of NR1-KD mice have neurochemical adaptations due to sustained NMDAR deficiency (graphically depicted in the left panel). Tyrosine hydroxylase (TH) levels and activity are reduced, dopamine transporter levels and activity are increased, and electrically stimulated dopamine release is reduced. Dopamine D2 autoreceptors are subsensitive to agonist and antagonist, suggesting hyperdopaminergia. Slice electrophysiology indicates that tonic firing of NR1-KD dopamine neurons is increased, but the induction of phasic firing by application of NMDA is impaired (top right panel). These neurochemical adaptations also impair phasic signaling by dampening dopamine overflow that normally occurs with high-frequency stimulation. When slices are electrically stimulated at frequencies that model phasic firing, there is no increase in dopamine relative to single-pulse stimulation (bottom left panel).

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