NMDA receptor antagonists influence early development of GABAergic interneurons in the mammalian striatum

Neurotransmitters influence a wide variety of developmental processes. We hypothesize that N-methyl-d-aspartate (NMDA) glutamate receptors influence proliferation of populations of forebrain neurons. As our model, we use a subclass of GABAergic striatal interneurons that express the calcium binding protein parvalbumin (PV). To separate proliferative and post-proliferative effects of NMDA receptor antagonists on PV neurons, we first determined the birth-date of rat striatum PV neurons at the coronal level selected for analysis. Dividing striatal progenitor cells were marked by intraperitoneal injections of 5'-bromodeoxyuridine (BrdU) given to timed pregnant rats at selected time points between embryonic days (E) 12-22. Double immunohistochochemistry for BrdU and PV is used in adult progeny to determine the time course of neurogenesis of striatal PV neurons. The results of the neurogenetic analysis were then used for rational timing of treatment with competitive (CGS19755) and non-competitive (MK-801) NMDA receptor antagonists. In comparison to pair-fed and vehicle-injected controls, gestational rats given CGS-19755 and MK-801 during the proliferative phase (E15-E18) showed a marked reduction of striatal PV neuron cell density as adults. In contrast, animals given NMDA antagonists during the post-proliferative period (E18-E21) showed no significant reduction in PV neuron cell density compared to pair-fed controls. These results suggest that glutamate influences cell proliferation of a population of striatal neurons by an NMDA-mediated mechanism, suggesting a novel role for excitatory amino acids in early forebrain development.