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Role of glutamate N-Methyl-D-Aspartate receptor surface trafficking in the firing pattern of midbrain dopaminergic neurons

Abstract : Midbrain dopaminergic (DA) neurons play several key functions in the brain such as the processing of salient information but are also associated with the emergence of pathologies including Parkinson’s disease and drug addiction. Because these processes have in common to modify the firing activity of midbrain DA neurons, it is of crucial importance to understand the mechanisms underlying this activity. Among the various ions channels and receptors involved in the generation of the firing activity of midbrain DA neurons, glutamate N-methyl-D-aspartate receptors (NMDAR) and calciumdependent potassium SK channels strongly modulate the firing pattern and functionally interact in several neuronal types including DA neurons. However, the mechanisms by which they regulate the firing pattern are poorly understood. Since the functional coupling between NMDAR and SK channels depends on their relative membrane distribution, we hypothesized that the lateral diffusion of NMDAR, which regulates the surface localization of the receptor, could play a role in the firing pattern of midbrain DA neurons through the modulation of SK channel function. We showed first that membrane NMDAR was highly mobile in cultured DA neurons. Alteration of its surface trafficking by a crosslink with NMDAR antibodies profoundly modified the regularity of the firing pattern of DA neurons in midbrain slices, whereas pharmacological blockade of NMDAR did not affect it. Furthermore, a SK channel blocker, which induces a similar change in the firing regularity in control conditions, was less effective when NMDAR surface trafficking was altered. Taken together, these results demonstrate that NMDAR surface dynamics modulate the firing pattern of midbrain DA neurons by regulating SK channel function.
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https://tel.archives-ouvertes.fr/tel-01764335
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Submitted on : Wednesday, April 11, 2018 - 7:00:06 PM
Last modification on : Tuesday, March 16, 2021 - 4:14:02 PM

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Laetitia Etchepare. Role of glutamate N-Methyl-D-Aspartate receptor surface trafficking in the firing pattern of midbrain dopaminergic neurons. Neurons and Cognition [q-bio.NC]. Université de Bordeaux, 2017. English. ⟨NNT : 2017BORD0849⟩. ⟨tel-01764335⟩

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