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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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Oscillations persist under SK current blockade.(A) The blockade moderately increases the frequency of oscillations. (B) A very weak applied depolarization (320 pA) is enough to block the oscillations. (C) NMDA receptor activation elevates the frequency as effectively as in the presence of the SK current. (D) A moderate NMDAR activation rescues the neuron from the blockade of oscillations caused by applied depolarization. (E,F) The dependence of the frequency on the NMDAR conductance and the applied current. The plots are similar to Fig. 2D and Fig. 4C respectively, but both horizontal scales are expanded and depolarization block occurs at lower values than with the SK current.
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pone-0069984-g005: Oscillations persist under SK current blockade.(A) The blockade moderately increases the frequency of oscillations. (B) A very weak applied depolarization (320 pA) is enough to block the oscillations. (C) NMDA receptor activation elevates the frequency as effectively as in the presence of the SK current. (D) A moderate NMDAR activation rescues the neuron from the blockade of oscillations caused by applied depolarization. (E,F) The dependence of the frequency on the NMDAR conductance and the applied current. The plots are similar to Fig. 2D and Fig. 4C respectively, but both horizontal scales are expanded and depolarization block occurs at lower values than with the SK current.

Mentions: On the other hand, the neuron demonstrates calcium-independent firing, as we mentioned in the Introduction. This requires a calcium-independent repolarizing mechanism. We have introduced a voltage-dependent potassium current to play this role. The calibration of the current resulted in the half-activation around −50 mV, slow activation (∼62 ms) and even slower deactivation (∼362 ms). The slowness of the current, and especially that its deactivation is much slower than activation, suggests the ERG current as the best candidate [35]. The current sustains pacemaking in the absence of the SK current, but only in a very small interval of applied depolarization (Fig. 5 A&B). We found that this property is achieved by a close match between the half-activations of the Ca2+ current and our ERG current in the model. Our cline analysis below explains this connection. The slowness of the current determines that only moderate increase in the frequency of background firing is observed upon the blockade of the SK current (Fig. 5A), which matches experimental data [36], [37]. The difference between the activation and deactivation timescales allows the ERG current to maintain the voltage waveform with a narrow peak and slow release from the hyperpolarized state. Additionally, we slow down the activation of the current to make it negligible in the presence of the SK current (Fig. 6). This makes the SK current dominant in the oscillatory cycle. Upon the blockade of the SK current, the switch from it to the ERG current determines the narrowing range of applied depolarization where the neuron sustains oscillations.


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

Ha J, Kuznetsov A - PLoS ONE (2013)

Oscillations persist under SK current blockade.(A) The blockade moderately increases the frequency of oscillations. (B) A very weak applied depolarization (320 pA) is enough to block the oscillations. (C) NMDA receptor activation elevates the frequency as effectively as in the presence of the SK current. (D) A moderate NMDAR activation rescues the neuron from the blockade of oscillations caused by applied depolarization. (E,F) The dependence of the frequency on the NMDAR conductance and the applied current. The plots are similar to Fig. 2D and Fig. 4C respectively, but both horizontal scales are expanded and depolarization block occurs at lower values than with the SK current.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0069984-g005: Oscillations persist under SK current blockade.(A) The blockade moderately increases the frequency of oscillations. (B) A very weak applied depolarization (320 pA) is enough to block the oscillations. (C) NMDA receptor activation elevates the frequency as effectively as in the presence of the SK current. (D) A moderate NMDAR activation rescues the neuron from the blockade of oscillations caused by applied depolarization. (E,F) The dependence of the frequency on the NMDAR conductance and the applied current. The plots are similar to Fig. 2D and Fig. 4C respectively, but both horizontal scales are expanded and depolarization block occurs at lower values than with the SK current.
Mentions: On the other hand, the neuron demonstrates calcium-independent firing, as we mentioned in the Introduction. This requires a calcium-independent repolarizing mechanism. We have introduced a voltage-dependent potassium current to play this role. The calibration of the current resulted in the half-activation around −50 mV, slow activation (∼62 ms) and even slower deactivation (∼362 ms). The slowness of the current, and especially that its deactivation is much slower than activation, suggests the ERG current as the best candidate [35]. The current sustains pacemaking in the absence of the SK current, but only in a very small interval of applied depolarization (Fig. 5 A&B). We found that this property is achieved by a close match between the half-activations of the Ca2+ current and our ERG current in the model. Our cline analysis below explains this connection. The slowness of the current determines that only moderate increase in the frequency of background firing is observed upon the blockade of the SK current (Fig. 5A), which matches experimental data [36], [37]. The difference between the activation and deactivation timescales allows the ERG current to maintain the voltage waveform with a narrow peak and slow release from the hyperpolarized state. Additionally, we slow down the activation of the current to make it negligible in the presence of the SK current (Fig. 6). This makes the SK current dominant in the oscillatory cycle. Upon the blockade of the SK current, the switch from it to the ERG current determines the narrowing range of applied depolarization where the neuron sustains oscillations.

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