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Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

Ha J, Kuznetsov A - PLoS ONE (2013)

Bottom Line: We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli.Standard cline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations.The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biological Modeling, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA) neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR) activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR) activation or applied depolarization) block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard cline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG), which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.

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Related in: MedlinePlus

Oscillations of the voltage and Ca2+ concentration.(A) At the onset of high-frequency oscillations, the amplitude of Ca2+ concentration is dramatically reduced (dashed: Ca2+ concentration; solid: the voltage). (B) Oscillations are presented by a closed loop in the Ca2+-V plane. The oscillations circumscribe folding of the voltage cline (dotted). (C) The oscillations are blocked if the intersection of the voltage and Ca2+ clines interrupts the loop.
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pone-0069984-g008: Oscillations of the voltage and Ca2+ concentration.(A) At the onset of high-frequency oscillations, the amplitude of Ca2+ concentration is dramatically reduced (dashed: Ca2+ concentration; solid: the voltage). (B) Oscillations are presented by a closed loop in the Ca2+-V plane. The oscillations circumscribe folding of the voltage cline (dotted). (C) The oscillations are blocked if the intersection of the voltage and Ca2+ clines interrupts the loop.

Mentions: To explain the mechanism underlying the frequency responses, we simplify the model by blocking our ERG current. As a result, the model is reduced to a system of two variables: the voltage and calcium concentration (Eq. 1&2). Fig. 8A shows time series for these two variables at the onset of NMDA-evoked high-frequency oscillation. To show a good correspondence with the reconstructed morphology model that includes the spike-producing currents, we show the same transition in Fig. S1A of Supplement S1. In Fig. 8A, at the onset, the amplitude of Ca2+ oscillations is dramatically reduced. This underlies the frequency increase. A less steep voltage dependence of the NMDA current compared to the Ca2+ current determines the decrease in the amplitude of Ca2+ concentration. To explain this, we introduce a simple mathematical tool.


Interaction of NMDA receptor and pacemaking mechanisms in the midbrain dopaminergic neuron.

Ha J, Kuznetsov A - PLoS ONE (2013)

Oscillations of the voltage and Ca2+ concentration.(A) At the onset of high-frequency oscillations, the amplitude of Ca2+ concentration is dramatically reduced (dashed: Ca2+ concentration; solid: the voltage). (B) Oscillations are presented by a closed loop in the Ca2+-V plane. The oscillations circumscribe folding of the voltage cline (dotted). (C) The oscillations are blocked if the intersection of the voltage and Ca2+ clines interrupts the loop.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3716766&req=5

pone-0069984-g008: Oscillations of the voltage and Ca2+ concentration.(A) At the onset of high-frequency oscillations, the amplitude of Ca2+ concentration is dramatically reduced (dashed: Ca2+ concentration; solid: the voltage). (B) Oscillations are presented by a closed loop in the Ca2+-V plane. The oscillations circumscribe folding of the voltage cline (dotted). (C) The oscillations are blocked if the intersection of the voltage and Ca2+ clines interrupts the loop.
Mentions: To explain the mechanism underlying the frequency responses, we simplify the model by blocking our ERG current. As a result, the model is reduced to a system of two variables: the voltage and calcium concentration (Eq. 1&2). Fig. 8A shows time series for these two variables at the onset of NMDA-evoked high-frequency oscillation. To show a good correspondence with the reconstructed morphology model that includes the spike-producing currents, we show the same transition in Fig. S1A of Supplement S1. In Fig. 8A, at the onset, the amplitude of Ca2+ oscillations is dramatically reduced. This underlies the frequency increase. A less steep voltage dependence of the NMDA current compared to the Ca2+ current determines the decrease in the amplitude of Ca2+ concentration. To explain this, we introduce a simple mathematical tool.

Bottom Line: We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli.Standard cline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations.The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biological Modeling, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Dopamine neurotransmission has been found to play a role in addictive behavior and is altered in psychiatric disorders. Dopaminergic (DA) neurons display two functionally distinct modes of electrophysiological activity: low- and high-frequency firing. A puzzling feature of the DA neuron is the following combination of its responses: N-methyl-D-aspartate receptor (NMDAR) activation evokes high-frequency firing, whereas other tonic excitatory stimuli (α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR) activation or applied depolarization) block firing instead. We suggest a new computational model that reproduces this combination of responses and explains recent experimental data. Namely, somatic NMDAR stimulation evokes high-frequency firing and is more effective than distal dendritic stimulation. We further reduce the model to a single compartment and analyze the mechanism of the distinct high-frequency response to NMDAR activation vs. other stimuli. Standard cline analysis shows that the mechanism is based on a decrease in the amplitude of calcium oscillations. The analysis confirms that the nonlinear voltage dependence provided by the magnesium block of the NMDAR determine its capacity to elevate the firing frequency. We further predict that the moderate slope of the voltage dependence plays the central role in the frequency elevation. Additionally, we suggest a repolarizing current that sustains calcium-independent firing or firing in the absence of calcium-dependent repolarizing currents. We predict that the ether-a-go-go current (ERG), which has been observed in the DA neuron, is the best fit for this critical role. We show that a calcium-dependent and a calcium-independent oscillatory mechanisms form a structure of interlocked negative feedback loops in the DA neuron. The structure connects research of DA neuron firing with circadian biology and determines common minimal models for investigation of robustness of oscillations, which is critical for normal function of both systems.

Show MeSH
Related in: MedlinePlus