Resistance of gonadotropin-releasing hormone neurons to glutamatergic neurotoxicity

Although many studies provide evidence that glutamatergic pathways regulate the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalam us, it is controversial as to whether they act directly upon GnRH neurons. The aim of the current study was to determine whether GnRH neurons are susc eptible to the neurotoxic actions of specific glutamate agonists (N-methyl- D-aspartate[NMDA] and kainic acid), the rationale being that neurotoxic los s of GnRH neurons would provide evidence that the perikarya possess specifi c classes of glutamate receptor. Unilateral 1-mu l injections of NMDA (12-1 20 mM), kainic acid (0.5-2.5 mM), or vehicle were stereotaxically directed at the preoptic area (mPOA)/diagonal band of Broca (dbB) in the region of t he organum vasculosum of the lamina terminalis (OVLT) of male adult hamster s (Phodopus sungorus), The number and appearance of GnRH neurons were deter mined by immunocytochemistry 3-8 days later, The morphology of GnRH neurons in the vicinity of the injection sites appeared normal after both kainic a cid and NMDA treatment, and there was no significant decrease in the number s of GnRH perikarya identified following these treatments. Both agonists ca used massive cellular loss when injected directly into cortical areas and s triatum, In the experimental studies, there was little neuronal loss within the mPOA or dbB after either toxin, despite clear neuronal loss in areas a djacent to the injection sites, including ventral striatum and olfactory co rtex. In follow-up studies, immunocytochemical and in situ hybridisation an alysis of the NMDAR1 and NMDAR2 glutamate receptor subunits confirmed their widespread distribution in regions containing GnRH perikarya, but no coloc alization within GnRH neurons was observed. The susceptibility of neural ar eas to NMDA neurotoxicity did not correlate with any difference in the regi onal expression of these glutamate receptor subunits. The resistance of GnR H neurons to the neurotoxic actions of two different glutamate agonists and the failure to detect colocalisation of NMDAR1 or NMDAR2 subunits within G nRH perikarya are consistent with the notion that the effects of glutamate upon GnRH secretion are not exerted directly upon GnRH cell bodies. (C) 199 9 Elsevier Science Inc.