(Scanned from the applicant's description): Despite intense investigation, the mechanisms underlying reproductive aging in females remains poorly understood. A hypothalamic defect is suggested to play a role, as prior to becoming acyclic, middle-aged rats display a significant attenuation of the proestrous LH surge and possess a significantly lower number of activated GnRH neurons in the hypothalamus. We hypothesized that the decreased activation of GnRH neurons on proestrus in the middle-aged rat could be due to a defect in the glutamate system, which is a major excitatory transmitter system regulating GnRH secretion. Our preliminary studies support this hypothesis as we demonstrated that the GnRH response to glutamate agonists is significantly attenuated in the middle-aged rat on proestrous. The mechanism responsible for the attenuated GnRH response to glutamate in the middle-aged proestrous rat remains unclear and is the primary focus of this grant.
Aim 1 will use microdialysis to measure glutamate and aspartate release rates in the hypothalamus of the middle-aged and young proestrous rat in order to determine whether there is a compromised excitatory amino drive to GnRH neurons.
Aim 2 will establish whether the reduced glutamate responsiveness in the middle-aged rat on proestrus could be due to an age-related reduction in ionotropic glutamate receptors in the hypothalamus.
Aim 3 will examine the status of anchoring/clustering proteins for glutamate receptors (PSD95, Chapsyn-1 10, GRIP) in the middle-aged proestrous rat since a defect in these proteins would lead to ineffective synaptic targeting, clustering and anchoring of glutamate receptors, with a corresponding loss of glutamate action.
Aim 4 will determine whether an age-related defect exists in the nitric oxide (NO) system in the hypothalamus, since NO is a major regulator of GnRH neuronal activation and a key mediator of glutamate effects. To prove causation between an identified defect and the attenuated LH surge, we will use retroviral gene transfer technology to correct the defect and see if this leads to reinstatement of the LH surge and extends cyclicity. As a whole, the proposed studies will provide important insights as to why glutamate signaling is compromised in the hypothalamus of the middle-aged rat, and will advance our understanding of reproductive aging.
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