EXCITATORY AMINO ACIDS AND THE CONTROL OF REPRODUCTION

Approximately 16% of US couples remain involuntarily childless or
experience major fertility problems. Although amenorrhea appears to be
one of the principal causes of human infertility, the underlying
neuroendocrine pathways responsible for its occurrence are poorly
understood. On the other hand, it is already well established that
luteinizing hormone-releasing hormone (LHRH) acts as the primary
neuroendocrine link between the central nervous system and the rest of
the reproductive axis. Consequently, a deeper understanding of the
neural circuitry that controls the pulsatile and surge patterns of LHRH
secretion should help to elucidate the underlying causes of centrally-
originating reproductive disorders. In the proposed study, a series of
non-invasive experiments will be performed to provide evidence that
excitatory amino acid (EAA) receptors play a major role in the control
of LHRH neuronal function. The results are expected to demonstrate the
EAA receptors are critically involved in the generation and modulation
of pulsatile LHRH secretion (Specific Aim #1) and that EAA receptors of
both the N-methyl-D-aspartate (NMDA) and kainate sub-types are critically
involved in the generation of the preovulatory LH surge (Specific Aim
#2). Furthermore, the results are expected to demonstrate that at the
time of puberty the LHRH neurons of the preoptic area primarily express
EAA receptor of the NMDA sub-type while those of the arcuate nuclei
primarily express EAA receptors of the kainate sub-type (Specific Aim
#3). It is predicted that expression of these receptors in LHRH neurons
first occurs during the peripubertal period and plays a pivotal role in
triggering sexual maturation. The involvement of EAA receptors in
regulating the pattern of LHRH secretion (Specific Aims #1 & 2) will be
examined in vivo by administering various EAA agonists and antagonists
and monitoring alterations in the pulsatile or surge patterns of LH
and/or LHRH secretion. Elucidation of the neural circuits through which
EAAs influence the activity of LHRH neurons (Specific Aims #3) will be
investigated in vitro using combined immunocytochemistry and in situ
hybridization to demonstrate co-localization of either NMDA or kainate
receptor MRNAS within LHRH neurons. It is envisioned that the results
will significantly further our understanding of the neuroendocrine
control of puberty and reproductive function. In a broader context, they
should also help to lay the foundation for the development of novel
approaches to contraception and the treatment of human infertility.