GluN2D subunit-containing NMDA receptors regulate reticular thalamic neuron function and seizure susceptibility
Dinesh Y Gawande1, Gajanan P Shelkar1, Kishore Kumar S Narasimhan1
1Department of Pharmacology and Neuroscience, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Neurobiology of Disease
|April 9, 2023
Summary
The GluN2D subunit in thalamic neurons is crucial for regulating brain activity and seizure susceptibility. Its absence reduces neuronal firing and protects against seizures, offering insights into pediatric epilepsy.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Thalamic regulation influences attention, sensorimotor control, and seizure activity.
- NMDA receptor subunits GluN2C and GluN2D are concentrated in thalamic nuclei like the nucleus reticularis of the thalamus (nRT).
- Previous studies showed GluN2C deletion had minimal impact on nRT neuron excitability.
Purpose of the Study:
- To investigate the specific role of the GluN2D subunit in thalamic circuitry and function.
- To determine the impact of GluN2D dysfunction on neuronal excitability, neurotransmission, and seizure susceptibility.
- To explore the link between GluN2D and pediatric epilepsy.
Main Methods:
- Utilized genetic ablation of the GluN2D subunit in mouse models.
- Examined depolarization- and hyperpolarization-induced firing patterns in nRT neurons.
- Assessed inhibitory neurotransmission in the ventrobasal thalamus (VB).
- Generated a conditional knockout model deleting GluN2D from parvalbumin (PV)-positive neurons.
- Evaluated seizure resistance (pentylenetetrazol-induced) and anesthetic sensitivity (isoflurane).
- Analyzed the expression of other GluN2 subunits and GABA receptors.
Main Results:
- GluN2D ablation reduced spike frequency and burst firing in nRT neurons.
- Reduced inhibitory neurotransmission was observed in the VB.
- Conditional deletion of GluN2D in PV neurons mimicked these effects on excitability and neurotransmission.
- Mice with GluN2D downregulation in PV neurons exhibited seizure resistance and altered anesthetic sensitivity.
- GluN2D deletion affected the expression of other NMDA receptor subunits and GABA receptors in nRT.
Conclusions:
- GluN2D-containing NMDA receptors play a critical role in regulating thalamic circuit function.
- Dysregulation of GluN2D contributes to altered neuronal excitability and neurotransmission.
- GluN2D subunit is a key factor in seizure susceptibility, relevant to GRIN2D-associated epilepsy.
- Targeting GluN2D may offer therapeutic potential for certain types of epilepsy.
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