Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats

Singh, Meharvan; Meyer, Edwin M.; Millard, William J.; Simpkins, James W.

doi:10.1016/0006-8993(94)91694-2

Cited by 440 publications

(237 citation statements)

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“…Furthermore, estrogens enhance visual and place memory (41) and working memory performances in rats (42) and facilitate cholinergic neurotransmission in the septal-hippocampal pathways (43). Several mechanisms have been reported by which estrogen acutely and more chronically potentiates memory-related synaptic plasticity in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Sarkar

Huang

Logan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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100

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L-type voltage-gated Ca 2؉ channels (VGCC) play an important role in dendritic development, neuronal survival, and synaptic plasticity. Recent studies have demonstrated that the gonadal steroid estrogen rapidly induces Ca 2؉ influx in hippocampal neurons, which is required for neuroprotection and potentiation of LTP. The mechanism by which estrogen rapidly induces this Ca 2؉ influx is not clearly understood. We show by electrophysiological studies that extremely low concentrations of estrogens acutely potentiate VGCC in hippocampal neurons, hippocampal slices, and HEK-293 cells transfected with neuronal L-type VGCC, in a manner that was estrogen receptor (ER)-independent. Equilibrium, competitive, and whole-cell binding assays indicate that estrogen directly interacts with the VGCC. Furthermore, a L-type VGCC antagonist to the dihydropyridine site displaced estrogen binding to neuronal membranes, and the effects of estrogen were markedly attenuated in a mutant, dihydropyridineinsensitive L-type VGCC, demonstrating a direct interaction of estrogens with L-type VGCC. Thus, estrogen-induced potentiation of calcium influx via L-type VGCC may link electrical events with rapid intracellular signaling seen with estrogen exposure leading to modulation of synaptic plasticity, neuroprotection, and memory formation.estrogen receptors ͉ signaling ͉ estradiol ͉ memory A large body of evidence shows that estrogens exert multiple rapid effects on the structure and function of neurons in a variety of brain regions, including the hippocampus (1). For example, estrogens rapidly potentiate kainite-induced currents in hippocampal neurons from wild-type (2) as well as from estrogenreceptor (ER)-␣ knockout (3) mice and induce rapid spine synapse formation in the CA1 hippocampus of ovariectomized (OVX) rats (4). Furthermore, acute application of estrogens to hippocampal slices increases NMDA and AMPA receptor transmission (5), induces long-term potentiation (LTP) and long-term depression (LTD) (6), and rapidly modulates neuronal excitability in rat medial amygdala (7) and hippocampus(8).It is well known that estrogens interact with cell membrane components and initiate signaling events leading to a rise in intracellular Ca 2ϩ , and activation of Src kinase, G protein-coupled receptor (GPCR), MAPK, PI3K/AKT, PKA, and adenylyl cyclase (9). The mechanism(s) by which estrogens induce these rapid and diverse effects remains largely unknown. Ca 2ϩ is a second messenger that can trigger the modification of synaptic efficacy. A plasticity-induction protocol like repetitive low-frequency synaptic stimulation (10) induces the elevation of postsynaptic intracellular Ca 2ϩ . The level of intracellular Ca 2ϩ concentration can activate numerous kinases like CAMK, PKA, PKC, MAPK, PI3K, or phosphatases (11-15), which, respectively, phosphorylate or dephosphorylate ion channels, transcription factors, and other proteins that are involved in synaptic plasticity and memory formation. Because voltage-gated Ca 2ϩ channels (VGCC)-mediated extracellular Ca ...

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Section: Discussionmentioning

confidence: 99%

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Sarkar

Huang

Logan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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100

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“…Each of these have been associated with E 2 regulation of neuronal function and survival (Singh et al, 1994;McEwen et al, 1997;Mor et al, 1999;Woolley, 1999;Brinton, 2001;McEwen, 2001;Brinton, 2002, 2003a). Of these pathways, PI3K has the potential for activating a host of downstream signaling cascades (Yin et al, 1998;Simoncini et al, 2000;Alexaki et al, 2004;Ghisletti et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor Protein Interaction with Phosphatidylinositol 3-Kinase Leads to Activation of Phosphorylated Akt and Extracellular Signal-Regulated Kinase 1/2 in the Same Population of Cortical Neurons: A Unified Mechanism of Estrogen Action

Mannella¹,

Brinton²

2006

J. Neurosci.

190

189

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17␤-Estradiol (E 2 )-induced neuroprotection is dependent on mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling cascades. We sought to determine whether E 2 neuroprotective mechanisms are mediated by a unified signaling cascade activated by estrogen receptor (ER)-PI3K interaction within the same population of neurons or whether E 2 activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are independent signaling events in different neuronal populations. Immunoprecipitation of E 2 -treated cortical neurons was conducted to determine a protein-protein interaction between ER and the PI3K regulatory subunit p85. Subsequently, cortical neurons were treated with E 2 alone or in presence of MAPK inhibitors or PI3K inhibitors. Results of these analyses indicated a protein-protein interaction between ER and p85 that was time-dependent and consistent with the temporal profile for generation of Akt (pAkt) and ERK1/2 phosphorylation (pERK1/2). E 2 -induced phosphorylation of Akt, was first apparent at 10 min and maximal at 30 min. Simultaneously, E 2 -induced pERK1/2 was first apparent at 5-10 min and maximal at 30 min. Inhibition of PI3K completely blocked E 2 activation of pAkt at 10 and 30 min and blocked E 2 activation of ERK1/2 at 10 min, which revealed a PI3K-independent activation of ERK at 30 min. Double immunocytochemical labeling for pERK1/2 and pAkt demonstrated that E 2 induced both signaling pathways in the same neurons. These results indicate a unified signaling mechanism for rapid E 2 action that leads to the coordinated activation of both pERK1/2 and pAkt in the same population of neurons. Implications of these results for understanding estrogen mechanism of action in neurons and therapeutic development are considered.

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“…Cholinergic neurons are essential for learning and memory processes (7,24). Biomakers including choline acetyltransferase and NGF have been shown to be important for the function of cholinergic neurons (17).…”

Section: Resultsmentioning

confidence: 99%

Effect of Dietary ^|^gamma;-Aminobutyric Acid on the Nerve Growth Factor and the Choline Acetyltransferase in the Cerebral Cortex and Hippocampus of Ovariectomized Female Rats

Tujioka

Thanapreedawat

Yamada

et al. 2014

J Nutr Sci Vitaminol

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Summary The brain protein synthesis and the plasma concentration of growth hormone (GH) is sensitive to the dietary g-aminobutyric acid (GABA) in ovariectomized female rats; however, the role of dietary GABA on biomarkers including nerve growth factor (NGF) and choline acetyltransferase for the function of cholinergic neurons remains unknown in ovariectomized female rats. The purpose of this study was to determine whether the dietary GABA affects the concentration and mRNA level of NGF, and the activity of choline acetyltransferase in the brains of ovariectomized female rats. Experiments were done on two groups of 24-wk-old ovariectomized female rats given 0 or 0.5% GABA added to a 20% casein diet. The concentrations of NGF and activities of choline acetyltransferase in the cerebral cortex and hippocampus, and mRNA level of NGF in the hippocampus increased significantly with the 20% casein10.5% GABA compared with the 20% casein diet alone. In the hippocampus, the mRNA level of NGF significantly correlated with the NGF concentration (r50. 714, p,0.01). These results suggest that the administration of GABA to ovariectomized female rats is likely to control the mRNA level and concentration of NGF and cause an increase in the activity of choline acetyltransferase in the brains.

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Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats

Cited by 440 publications

References 36 publications

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Estrogen Receptor Protein Interaction with Phosphatidylinositol 3-Kinase Leads to Activation of Phosphorylated Akt and Extracellular Signal-Regulated Kinase 1/2 in the Same Population of Cortical Neurons: A Unified Mechanism of Estrogen Action

Effect of Dietary ^|^gamma;-Aminobutyric Acid on the Nerve Growth Factor and the Choline Acetyltransferase in the Cerebral Cortex and Hippocampus of Ovariectomized Female Rats

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Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats

Cited by 440 publications

References 36 publications

Estrogens directly potentiate neuronal L-type Ca 2+ channels

Estrogens directly potentiate neuronal L-type Ca 2+ channels

Estrogen Receptor Protein Interaction with Phosphatidylinositol 3-Kinase Leads to Activation of Phosphorylated Akt and Extracellular Signal-Regulated Kinase 1/2 in the Same Population of Cortical Neurons: A Unified Mechanism of Estrogen Action

Effect of Dietary ^|^gamma;-Aminobutyric Acid on the Nerve Growth Factor and the Choline Acetyltransferase in the Cerebral Cortex and Hippocampus of Ovariectomized Female Rats

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Estrogens directly potentiate neuronal L-type Ca ²⁺ channels

Estrogens directly potentiate neuronal L-type Ca ²⁺ channels