Activity-dependent regulation of NMDA receptors in substantia nigra dopaminergic neurones.

Wild AR, Jones S, Gibb AJ. J Physiol. 2014 Feb 15;592(Pt 4):653-68. doi: 10.1113/jphysiol.2013.267310. Epub 2013 Dec 16. Because Madhan is investigating the possibility of physical activity causing a downregulation in NMDA-Receptors, this paper caught my eye. In this study, the authors looked how dopaminergic cells show acute rundown in NMDAR currents in brain slices containing the substantia nigra (the area known to suffer massive cell loss in Parkinson’s Disease) after repeated stimulation. They used whole-cell patch clamp to recorded NMDAR currents after repeated doping of the perfusion medium with NMDA. They found that rundown occurred in a couple of different ways. Some of it was dependent on calcium influx (NMDAR allows calcium ions to pass through in addition to sodium ions), which they could show by voltage clamping the cell near the reversal of calcium. However, even after replacing extracellular Ca2+ with Ba2+, significant rundown occurred, suggesting there are calcium-independent mechanisms in effect too. They suspected that the Glu2NB receptor subunit was involved, but were not able to block current rundown after using a Glu2NB-preferring antagonist. They were, however, able to block current rundown with a dynamin antagonist, suggesting that receptor regulation occurs through clathrin-mediated endocytosis. One thing that was pretty cool was how they also patched on to GABAergic neurons in the same region and found that they had a higher rate of rundown, suggesting that they have a built in mechanism for protecting themselves against excitotoxicity that dopaminergic neurons lack. -DH