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bioRxiv · 10.1101/2020.07.26.222125

Glutamate NMDA receptors containing GluN2C subunit relay the reward signal of the ventral tegmental area upon dorsal raphe stimulation

Hernandez, G.·Poirier, E.·Lebied, K.·Kouwenhoven, W. M.·Levesque, D.·Rompre, P.-P.
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Abstract

BackgroundGlutamate relays a reward signal from the dorsal raphe (DR) to the ventral tegmental area (VTA). However, the role of the different subtypes of N-methyl-D-aspartate (NMDA) receptors is complex and not clearly understood. Therefore, we measured NMDA receptors subunits expression in limbic brain areas. In addition, we studied the effects of VTA down-regulation of GluN2C NMDA receptor on the reward signal that arises from DR electrical stimulation. MethodsUsing qPCR, we identified the relative composition of the different Grin2a-d subunits of the NMDA receptors in several brain areas. Then, we used fluorescent in situ hybridization (FISH) to evaluate the colocalization of Grin2c and tyrosine hydroxylase (TH) mRNA in VTA neurons. To assess the role of GluN2C in brain stimulation reward; we downregulated this receptor using small interfering RNA (siRNA) in rats self-stimulating for electrical pulses delivered to the DR. To delineate further the specific role of GluN2C in relaying the reward signal, we pharmacologically altered the function of VTA NMDA receptors by bilaterally microinjecting the NMDA receptor antagonist PPPA. ResultsWe identified GluN2C as the most abundant subunit of the NMDA receptor expressed in the VTA. FISH revealed that about 50% of TH-positive neurons colocalize with Grin2c transcript. siRNA manipulation produced a selective down-regulation of the GluN2C protein subunit and a significant reduction in brain stimulation reward. Interestingly, PPPA enhanced brain stimulation reward, but only in rats that received the nonactive RNA sequence. ConclusionThe present results suggest that VTA glutamate neurotransmission relays a reward signal initiated by DR stimulation by acting on GluN2C NMDA receptors. HighlightsO_LIWith the use of qpCR we identified the NMDA receptor composition in different brain areas C_LIO_LIUsing Double-fluorescent in situ hybridization we demonstrated that TH+ cells contain the NMDA Glun2C subunit C_LIO_LIUsing deep brain stimulation of the dorsal raphe and small interfering RNA we demonstrate that the reward signal is carried to VTA neurons through activation of Glun2C NMDA receptors. C_LI

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Hernandez, G., Poirier, E., Lebied, K., Kouwenhoven, W. M., Levesque, D., Rompre, P.-P.. 2020-07-26. Glutamate NMDA receptors containing GluN2C subunit relay the reward signal of the ventral tegmental area upon dorsal raphe stimulation. https://doi.org/10.1101/2020.07.26.222125

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