Estrogen effects on different neurotransmitters in rat hippocampus : implications for cognitive function
Author: El-Bakri, Nahid Karrar
Date: 2004-12-03
Location: Hörsalen, plan 4, Novum, Karolinska Universitetssjukhuset, Huddinge
Time: 9.30
Department: Centrum för kirurgisk vetenskap CFSS / Center for Surgical Sciences CFSS
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.
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.
List of papers:
I. El-Bakri NK, Adem A, Suliman IA, Mulugeta E, Karlsson E, Lindgren JU, Winblad B, Islam A (2002). "Estrogen and progesterone treatment: effects on muscarinic M(4) receptor subtype in the rat brain. " Brain Res 948(1-2): 131-7
Pubmed
II. El-Bakri NK, Adem A, Mulugeta E, Karlsson E, Cedazo-Mingues, Winblad B, Islam A (2004). "Levels of hippocampal muscarinic M4 receptor subtype are rduced in estrogen receptor knockout mice." (Manuscript)
III. El-Bakri NK, Islam A, Suliman I, Lindgren U, Winblad B, Adem A (2004). "Ovariectomy and gonadal hormone treatment: effects on insulin-like growth factor-1 receptors in the rat brain." Growth Horm IGF Res 14(5): 388-93
Pubmed
IV. El-Bakri NK, Islam A, Zhu S, Elhassan A, Mohammed A, Winblad B, Adem A (2004). "Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors." J Cell Mol Med (Accepted)
I. El-Bakri NK, Adem A, Suliman IA, Mulugeta E, Karlsson E, Lindgren JU, Winblad B, Islam A (2002). "Estrogen and progesterone treatment: effects on muscarinic M(4) receptor subtype in the rat brain. " Brain Res 948(1-2): 131-7
Pubmed
II. El-Bakri NK, Adem A, Mulugeta E, Karlsson E, Cedazo-Mingues, Winblad B, Islam A (2004). "Levels of hippocampal muscarinic M4 receptor subtype are rduced in estrogen receptor knockout mice." (Manuscript)
III. El-Bakri NK, Islam A, Suliman I, Lindgren U, Winblad B, Adem A (2004). "Ovariectomy and gonadal hormone treatment: effects on insulin-like growth factor-1 receptors in the rat brain." Growth Horm IGF Res 14(5): 388-93
Pubmed
IV. El-Bakri NK, Islam A, Zhu S, Elhassan A, Mohammed A, Winblad B, Adem A (2004). "Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors." J Cell Mol Med (Accepted)
Issue date: 2004-11-12
Publication year: 2004
ISBN: 91-7140-118-0
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