Effects of Chronic NMDA ‐ NR 2b Inhibition in the Median Eminence of the Reproductive Senescent Female Rat

• Published in: Journal of neuroendocrinology 2013-10, Vol.25 (10), p.887-897
• Main Authors: Kermath, B. A., Riha, P. D., Sajjad, A., Gore, A. C.
• Format: Article
• Language: English
• ISSN: 0953-8194; 1365-2826
• DOI: 10.1111/jne.12087

Gonadotrophin‐releasing hormone ( G n RH ) neurones of the hypothalamic‐pituitary‐gonadal ( HPG ) axis drive reproductive function and undergo age‐related decreases in activation during the transition to reproductive senescence. Decreased G n RH secretion from the median eminence ( ME ) partially arises from attenuated glutamatergic signalling via the NMDA receptor ( NMDAR ) and may be a result of changing NMDAR stoichiometry to favour NR 2b over NR 2a subunit expression with ageing. We have previously shown that the systemic inhibition of NR 2b‐containing receptors with ifenprodil, an NR 2b‐specific antagonist, stimulates parameters of luteinising hormone (used as a proxy for G n RH ) release in both young and middle‐aged females. In the present study, we chronically administered ifenprodil, an NR 2b‐specific antagonist, at the site of G n RH terminals in the ME or at G n RH perikarya in the preoptic area, in reproductively senescent middle‐aged female rats, aiming to determine whether NR 2b antagonism could restore aspects of reproductive functionality. Effects on oestrous cyclicity, serum hormones, and protein expression of G n RH , NR 2b and phosphorylated NR 2b ( T yr‐1472) in the ME were measured. Chronic ifenprodil treatment in the ME (but not the preoptic area) altered oestrous cyclicity by increasing the percentage of days spent in pro‐oestrus. This was accompanied by increased G n RH fluorescence intensity in the external ME zone and a greater proportion of G n RH terminals that co‐labelled with p NR 2b with treatment. We also observed changes in the relationships between protein immunofluorescence, serum hormone levels and other aspects of reproductive physiology in acyclic females, as revealed by bionetwork analysis. Together, these data support the hypothesis that NMDAR ‐ NR 2b expression and phosphorylation state play a role in reproductive senescence and highlight the ME as a major player in reproductive ageing.