Loss of NMDA receptor-dependent activity of dopaminergic neurons leads to development of depressive-like symptoms in mice

2016 ◽  
Vol 4 (Suppl. 2) ◽  
pp. A18.43
Author(s):  
Jan Rodriguez Parkitna
Keyword(s):  
Nmda Receptor ◽  
Dopaminergic Neurons ◽  
Dependent Activity

Transient High-Frequency Firing in a Coupled-Oscillator Model of the Mesencephalic Dopaminergic Neuron

2006 ◽  
Vol 95 (2) ◽  
pp. 932-947 ◽  
Author(s):  
Alexey S. Kuznetsov ◽  
Nancy J. Kopell ◽  
Charles J. Wilson
Keyword(s):  
Nmda Receptor ◽  
High Frequency ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Receptor Activation ◽  
Oscillator Model ◽  
Coupled Oscillator ◽  
Depolarization Block ◽  
Nmda Receptor Activation ◽  
Coupled Oscillator Model

Dopaminergic neurons of the midbrain fire spontaneously at rates <10/s and ordinarily will not exceed this range even when driven with somatic current injection. When driven at higher rates, these cells undergo spike failure through depolarization block. During spontaneous bursting of dopaminergic neurons in vivo, bursts related to reward expectation in behaving animals, and bursts generated by dendritic application of N-methyl-d-aspartate (NMDA) agonists, transient firing attains rates well above this range. We suggest a way such high-frequency firing may occur in response to dendritic NMDA receptor activation. We have extended the coupled oscillator model of the dopaminergic neuron, which represents the soma and dendrites as electrically coupled compartments with different natural spiking frequencies, by addition of dendritic AMPA (voltage-independent) or NMDA (voltage-dependent) synaptic conductance. Both soma and dendrites contain a simplified version of the calcium-potassium mechanism known to be the mechanism for slow spontaneous oscillation and background firing in dopaminergic cells. The compartments differ only in diameter, and this difference is responsible for the difference in natural frequencies. We show that because of its voltage dependence, NMDA receptor activation acts to amplify the effect on the soma of the high-frequency oscillation of the dendrites, which is normally too weak to exert a large influence on the overall oscillation frequency of the neuron. During the high-frequency oscillations that result, sodium inactivation in the soma is removed rapidly after each action potential by the hyperpolarizing influence of the dendritic calcium-dependent potassium current, preventing depolarization block of the spike mechanism, and allowing high-frequency spiking.

NMDA receptor modulation of the pedunculopontine tegmental nucleus underlies the motivational drive for feeding induced by midbrain dopaminergic neurons

2019 ◽  
Vol 1715 ◽  
pp. 134-147
Author(s):  
Grażyna Jerzemowska ◽  
Karolina Plucińska ◽  
Aleksandra Piwka ◽  
Kacper Ptaszek ◽  
Magdalena Podlacha ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Dopaminergic Neurons ◽  
Pedunculopontine Tegmental Nucleus ◽  
Tegmental Nucleus ◽  
Receptor Modulation ◽  
Midbrain Dopaminergic Neurons

scholarly journals A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain Dopaminergic Neurons

2010 ◽  
Vol 104 (1) ◽  
pp. 403-413 ◽  
Author(s):  
Collin J. Lobb ◽  
Charles J. Wilson ◽  
Carlos A. Paladini
Keyword(s):  
Nmda Receptor ◽  
Gaba Receptors ◽  
Dopaminergic Neurons ◽  
Firing Pattern ◽  
Activity Patterns ◽  
Burst Firing ◽  
Dynamic Clamp ◽  
Tonic Activity ◽  
Midbrain Dopaminergic Neurons

Dopaminergic neurons are subject to a significant background GABAergic input in vivo. The presence of this GABAergic background might be expected to inhibit dopaminergic neuron firing. However, dopaminergic neurons are not all silent but instead fire in single-spiking and burst firing modes. Here we present evidence that phasic changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism that triggers bursts and pauses in dopaminergic neurons. We find that spontaneous single-spiking is more sensitive to activation of GABA receptors than phasic N-methyl-d-aspartate (NMDA)-mediated burst firing in rat slices (P15–P31). Because tonic activation of GABAA receptors has previously been shown to suppress burst firing in vivo, our results suggest that the activity patterns seen in vivo are the result of a balance between excitatory and inhibitory conductances that interact with the intrinsic pacemaking currents observed in slices. Using the dynamic clamp technique, we applied balanced, constant NMDA and GABAA receptor conductances into dopaminergic neurons in slices. Bursts could be produced by disinhibition (phasic removal of the GABAA receptor conductance), and these bursts had a higher frequency than bursts produced by the same NMDA receptor conductance alone. Phasic increases in the GABAA receptor conductance evoked pauses in firing. In contrast to NMDA receptor, application of constant AMPA and GABAA receptor conductances caused the cell to go into depolarization block. These results support a bidirectional mechanism by which GABAergic inputs, in balance with NMDA receptor–mediated excitatory inputs, control the firing pattern of dopaminergic neurons.

scholarly journals Synergy of AMPA and NMDA Receptor Currents in Dopaminergic Neurons: A Modeling Study

2016 ◽  
Vol 10 ◽  
Author(s):  
Denis Zakharov ◽  
Christopher Lapish ◽  
Boris Gutkin ◽  
Alexey Kuznetsov
Keyword(s):  
Nmda Receptor ◽  
Dopaminergic Neurons ◽  
Modeling Study

NMDA receptor membrane dynamics tunes the firing pattern of midbrain dopaminergic neurons

2021 ◽  
Author(s):  
Laetitia Etchepare ◽  
Hélène Gréa ◽  
Pauline Durand ◽  
Delphine Bouchet ◽  
Laurent Groc
Keyword(s):  
Nmda Receptor ◽  
Dopaminergic Neurons ◽  
Firing Pattern ◽  
Membrane Dynamics ◽  
Receptor Membrane ◽  
Midbrain Dopaminergic Neurons

scholarly journals Brunner Syndrome associated MAOA dysfunction in human induced dopaminergic neurons results in dysregulated NMDAR expression and increased network activity

2019 ◽  
Author(s):  
Y. Shi ◽  
J.R. van Rhijn ◽  
M. Bormann ◽  
B. Mossink ◽  
M. Frega ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Aggressive Behavior ◽  
Single Cell ◽  
Dopaminergic Neurons ◽  
Receptor Expression ◽  
Monoamine Oxidase A ◽  
Network Activity ◽  
Electrode Arrays ◽  
Neuronal Function ◽  
Brunner Syndrome

AbstractMonoamine oxidase A (MAOA) is an enzyme that catalyzes the degradation of dopamine, noradrenaline, and serotonin. Regulation of monoamine neurotransmitter abundance through MAOA activity strongly affects motor control, emotion, and cognitive function. Mutations in MAOA cause Brunner Syndrome, which is characterized by impulsive aggressive behavior and mild intellectual disability (ID). The impaired MAOA activity in Brunner Syndrome patients results in bioamine aberration, but it is currently unknown how this affects neuronal function. MAOA is highly expressed in serotonergic and dopaminergic neurons, and dysfunction of both neurotransmission systems is associated with aggressive behavior in mice and humans. Research has so far mainly focused on the serotonergic system. Here, we generated human induced pluripotent stem cell-derived induced dopaminergic neurons (iDANs) from individuals with known MAOA mutations, to investigate MAOA-dependent effects on dopamine neuronal function in the context of Brunner Syndrome. We assessed iDAN lines from three patients and combined data from morphological analysis, gene expression, single-cell electrophysiology, and network analysis using micro-electrode arrays (MEAs). We observed mutation-dependent functional effects as well as overlapping changes in iDAN morphology. The most striking effect was a clear increase in N-methyl-D-aspartate (NMDA) receptor mRNA expression in all patient lines. A marked increase was also seen in coordinated network activity (network bursts) on the MEA in all patient lines, while single-cell intrinsic properties and spontaneous excitatory postsynaptic currents activity appeared normal. Together, our data indicate that dysfunction of MAOA leads to increased coordinated network activity in iDANs, possibly caused by increased synaptic NMDA receptor expression.

Sign in / Sign up

Export Citation Format

Share Document