AMPA, kainate, and NMDA receptor densities in the hippocampus of untreated male rats and females in estrus and diestrus

Palomero‐Gallagher, Nicola; Bidmon, Hans‐Jürgen; Zilles, Karl

doi:10.1002/cne.10638

Cited by 56 publications

(27 citation statements)

References 66 publications

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“…Specifically, males had significantly higher levels of NMDA binding in the dentate gyrus compared to females. In agreement with our finding, another study reported higher levels of NMDA binding in the dentate gyrus of males compared to estrus and diestrus females [59]. Males do have greater synaptic connectivity in the dentate gyrus compared to females [60], which may explain the higher levels of NMDA receptor expression observed in the previous [59] and present studies.…”

Section: Discussionsupporting

confidence: 82%

Sex Differences in Hippocampal Estradiol-Induced N-Methyl-<i>D</i>-Aspartic Acid Binding and Ultrastructural Localization of Estrogen Receptor-Alpha

et al. 2005

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Estradiol increases dendritic spine density and synaptogenesis in the CA1 region of the female hippocampus. This effect is specific to females, as estradiol-treated males fail to show increases in hippocampal spine density. Estradiol-induced spinogenesis in the female is dependent upon upregulation of the N-methyl-D-aspartic acid (NMDA) receptor as well as on non-nuclear estrogen receptors (ER), including those found in dendrites. Thus, in the male, the inability of estradiol to induce spinogenesis may be related to a failure of estradiol to increase hippocampal NMDA receptors as well as a paucity of dendritic ER. In the first experiment, we sought to investigate this possibility by assessing NMDA receptor binding, using [³H]-glutamate autoradiography, in estradiol-treated males and females. We found that while estradiol increases NMDA binding in gonadectomized females, estradiol fails to modulate NMDA binding in gonadectomized males. To further investigate sex differences in the hippocampus, we conducted a second separate, but related, ultrastructural study in which we quantified ERα-immunoreactivity (ERα-ir) in neuronal profiles in the CA1 region of the hippocampus in intact males and females in diestrus and proestrus. Consistent with previous reports in the female, we found ERα-ir in several extranuclear sites including dendrites, spines, terminals and axons. Statistical analyses revealed that females in proestrus had a 114.3% increase in ERα-labeled dendritic spines compared to females in diestrus and intact males. Taken together, these studies suggest that both the ability of estrogen to increase NMDA binding in the hippocampus and the presence of ERα in dendritic spines may contribute to the observed sex difference in estradiol-induced hippocampal spinogenesis.

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Section: Discussionsupporting

confidence: 82%

Sex Differences in Hippocampal Estradiol-Induced N-Methyl-<i>D</i>-Aspartic Acid Binding and Ultrastructural Localization of Estrogen Receptor-Alpha

et al. 2005

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“…Second, although an increase in excitability could, in theory, account for the increase in NMDAR transmission we and others observe (Woolley et al, 1997), it is difficult to explain how this mechanism could contribute to the delayed increase in AMPAR transmission we observe first at E48 (which is maintained at E72), because AMPARs are not voltage dependent. An obvious mechanism is an increase in expression of AMPARs, an interpretation that is supported by others (Palomero-Gallagher et al, 2003). Whether NMDAR transmission is elevated by increased excitability or through insertion of NMDARs into newly formed synapses as our data suggest requires additional investigation at the level of single synapses.…”

supporting

confidence: 50%

Estrogen-Induced Increase in the Magnitude of Long-Term Potentiation Occurs Only When the Ratio of NMDA Transmission to AMPA Transmission Is Increased

Smith¹,

McMahon²

2005

J. Neurosci.

170

191

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Elevated levels of estradiol enhance learning in mammals, including humans, likely a result of hormone-induced heightened plasticity at CA3-CA1 synapses. The increase in long-term potentiation (LTP) magnitude is considered to be a consequence of the estradiol-induced increase in dendritic spine density and NMDA receptor (NMDAR)-mediated transmission; however, direct evidence linking these changes together is lacking. Alternatively, alterations in GABAergic inhibition or presynaptic release probability could contribute. Here, we show in time course studies using hippocampal slices from estradiol-treated ovariectomized rats that the LTP magnitude is increased only when spine density is increased simultaneously with an increase in NMDAR transmission relative to AMPA receptor (AMPAR) transmission, with no role for alterations in GABAergic inhibition or release probability. With time after hormone treatment, AMPAR transmission gradually increases during the maintained increase in spine density and NMDAR transmission. Eventually, the balance between NMDAR and AMPAR transmission is reestablished, and the LTP magnitude is no longer increased. Blocking genomic estrogen receptors prevents the heightened spine density, NMDAR transmission, and LTP magnitude, suggesting a tight mechanistic coupling between these morphological and functional changes. Thus, we propose that the hormone-induced increase in functional synapse density alone is not sufficient to support heightened plasticity. Rather, estradiol increases LTP via enhancing NMDAR transmission, likely through receptor insertion into newly formed or preexisting synapses. Later, when excitability in the circuit is at its highest and spine density remains elevated, the LTP magnitude is no longer increased, probably as a consequence of the delayed increase in AMPAR transmission that resets the balance between NMDAR and AMPAR transmission.

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“…The hippocampus of male rats contains significantly more AMPA, kainate, and NMDA receptors than those of female rats. Female rats in diestrus have significantly higher AMPA receptor densities than female rats in estrus [30]. These conflicting data show that morphine potentiation by NMDA antagonists follows a complex mechanism that may depend on the antinociceptive assay used, the pain model, and other factors such as type of antagonist, dose, and gender.…”

Section: Discussionmentioning

confidence: 99%

Gender differences in paclitaxel-induced neuropathic pain behavior and analgesic response in rats

Hwang

Kim

et al. 2012

Korean J Anesthesiol

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BackgroundFemales show greater sensitivity than males to several modalities of experimental pain. However, the gender differences in paclitaxel-induced neuropathic pain have not been studied. The current study examined the gender differences in neuropathic pain behavior and the effect of analgesics in a paclitaxel-induced neuropathic pain model in rats.MethodsNeuropathic pain was induced by intraperitoneal injection of paclitaxel (2 mg/kg) on 4 alternate days in Sprague-Dawley rats of both genders. Mechanical allodynia was measured using a von Frey filament. The gender differences in analgesic responses were determined after administration of morphine (2 or 5 mg/kg), ketamine (2 or 5 mg/kg), or combined morphine (2 mg/kg) and ketamine (2 mg/kg).ResultsPaclitaxel induced mechanical allodynia, which began to manifest on day 4, peaked within 10 days, and plateaued for at least 2 months after the first paclitaxel injection. No gender difference in the manifestation of mechanical allodynia was observed. A 2 mg/kg dose of ketamine increased the mechanical threshold only in males. The 5 mg/kg dose of ketamine significantly increased the mechanical threshold in both genders. Morphine (2 and 5 mg/kg) dose-dependently increased the mechanical thresholds in both genders. The 2 mg/kg dose of ketamine enhanced the antinociceptive effect of 2 mg/kg morphine only in females.ConclusionsNo gender difference in paclitaxel-induced neuropathic pain or analgesic response to ketamine or morphine was observed in Sprague-Dawley rats. Low dose ketamine enhanced the analgesic effect of morphine on paclitaxel-induced mechanical allodynia but only in female rats.

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AMPA, kainate, and NMDA receptor densities in the hippocampus of untreated male rats and females in estrus and diestrus

Cited by 56 publications

References 66 publications

Sex Differences in Hippocampal Estradiol-Induced N-Methyl-<i>D</i>-Aspartic Acid Binding and Ultrastructural Localization of Estrogen Receptor-Alpha

Sex Differences in Hippocampal Estradiol-Induced N-Methyl-<i>D</i>-Aspartic Acid Binding and Ultrastructural Localization of Estrogen Receptor-Alpha

Estrogen-Induced Increase in the Magnitude of Long-Term Potentiation Occurs Only When the Ratio of NMDA Transmission to AMPA Transmission Is Increased

Gender differences in paclitaxel-induced neuropathic pain behavior and analgesic response in rats

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