Estrogen effects on different neurotransmitters in rat hippocampus : Implications for cognitive function

Abstract: The past decade has witnessed a growing interest in estrogens and their activity in the central nervous system, which extends beyond the reproductive functions. Estrogen is known to interact with different neurotransmitter systems. Ovariectomized rats were used in this thesis as a model to investigate the effect of ovarian hormones on the cholinergic system, the glutamate system and insulin-like growth factors with specific emphasis in the hippocampus. Using M4-toxin-1, a selective ligand for M4 muscarinic cholinergic receptor subtype, we observe that 17beta-estradiol but not progesterone reversed the ovariectomy-induced up regulation of the M4 subtype in the hippocampus of the rat brain (Paper I). Moreover, ovariectomy significantly reduced the exploratory activity of the rats but estradiol treatment reversed the activity back to normal. In order to investigate the levels of M4, and M1 muscarinic acetylcholine receptor subtypes in estrogen receptors knockout (ERKO) mice hippocampus, we used ERalphaKO and ERbetaKO in Paper II. Significant decrease of M4 but not M1 receptors subtype was noticed in both ERalphaKO and ERbetaKO mice, which suggest a selective suppression of M4 receptor subtype by estrogen. Both estrogen and IGF-I have a regulatory role on the cholinergic system. Moreover, there is interdependence in their cumulative action in neuronal differentiation, plasticity and neurodegeneration. Paper III focuses on estrogen effect on the IGF-I receptors in the ovariectomized rat brain. Estrogen significantly increased the IGF-I receptor density in different brain areas compared to ovariectomized rats. Moreover, estradiol treatment reduced the plasma IGF-I levels. These effects showed dose dependent modulator effect of ovarian hormones on IGF-I activity. The glutamate system is well known for its effect on memory functions. To study the effect of estrogen on the glutamatergic system, NMDA receptor changes in ovariectomized rats were investigated in Paper IV. Morris water maze was used to study behavioral changes. Ovariectomy severely impaired reference memory and increased MK-801 binding in the hippocampus. Estradiol treatment improved memory performance and reduced MK-801 binding back to normal level. The studies presented here provide insights into some mechanisms of estrogen effects on the cholinergic, glutamate and IGF-I systems. The present findings suggest that regulation of the M4 receptors, and possibly NMDA and IGF-I receptors, might be the underlying mechanism of estrogen effects on memory functions.