Role of glutamate NMDA receptors on the firing pattern of midbrain dopaminergic neurons
Midbrain dopaminergic (DA) neurons play several key functions in the brain such 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 calcium-dependent 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 the SK channel function. We showed first that membrane NMDAR was highly mobile on cultured DA neurons.
Alteration of its surface trafficking by a crosslink with NMDAR antibodies profoundly modify the regularity of the firing pattern of DA neurons in midbrain slices, whereas pharmacology blockade of NMDAR did not affect it. Furthermore, a SK channels 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 the SK channels function.
Keywords : glutamate NMDA receptors, surface trafficking, dopamine, firing pattern, crosslink, electrophysiologya
Publications : Varela JA, Dupuis JP, Etchepare L, Espana A, Cognet L, Groc L (2016a) Targeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices. Nat Commun 7:10947.
Etchepare L, Grea H, Durand P, Bouchet D, Groc L. Role of NMDAR surface trafficking in midbrain dopaminergic neurons. In preparation