Modulation of Ionotropic Glutamate Receptors by Neuroactive Steroids

Gibbs, Terrell T.; Yaghoubi, Nader; WeaverJr., Charles E.; Park-Chung, Mijeong; Russek, Shelley J.; Farb, David H.

doi:10.1007/978-1-59259-693-5_10

Cited by 24 publications

(18 citation statements)

References 114 publications

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“…Bulk PREGS concentrations in tissue homogenates have been estimated to be in the nanomolar range, yet NMDA receptors are significantly modulated by micromolar concentrations of this neurosteroid (Gibbs et al, 1999). Therefore, it has been hypothesized that PREGS may be focally released, and, using an antibody scavenger, we demonstrated that a PREGS-like neurosteroid is synaptically released in a retrograde manner from depolarized postsynaptic CA1 neurons.…”

Section: Discussionmentioning

confidence: 79%

“…Importantly, this effect is mediated by presynaptic NMDA receptors likely containing NR2D subunits, which are transiently expressed during the first week of life in the murine hippocampus (Wenzel et al, 1997a,b;Okabe et al, 1998). It is well established that PREGS is a positive allosteric modulator of NMDA receptors and it is expected to act by facilitating the actions of glutamate at presynaptic NMDA receptors (Gibbs et al, 1999). Given that the PREGS effect can be seen in the presence of tetrodotoxin, in which neurotransmitter release occurs in an action potentialindependent manner, this neurosteroid must significantly increase the efficacy and/or potency of low glutamate levels generated by quantal release.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a localized elevation in Ca 2ϩ influx through NMDA receptors could be responsible for the induction of plasticity. Two factors should contribute to this localized Ca 2ϩ elevation: (1) currents mediated by receptors containing the NR2B subunit have slow decay kinetics (Flint et al, 1997), and (2) currents mediated by these receptors should be potentiated during the brief application of PREGS (Gibbs et al, 1999). The Ca 2ϩ elevation could then activate protein kinases that are functional during development, such as cAMP-dependent protein kinase, which phosphorylates AMPA receptors and increases their con-ductance (Wang et al, 1991;Banke et al, 2000;Yasuda et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…1d), which have been shown to modulate NMDA receptor function (Gibbs et al, 1999). Analysis of cumulative probability distributions of individual cells by means of the KS test revealed a statistically significant effect of PREGS on mEPSC frequency in zero of nine neurons (10 M), three of four neurons (17 M), seven of eight neurons (25 M), six of six neurons (35 M), and seven of eight neurons (50 M).…”

Section: Pregs Induces a Long-lasting Increase In Mepsc Frequency Durmentioning

confidence: 97%

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Neurosteroid-Induced Plasticity of Immature Synapses via Retrograde Modulation of Presynaptic NMDA Receptors

Mameli

Carta²,

Partridge³

et al. 2005

J. Neurosci.

106

122

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Neurosteroids are produced de novo in neuronal and glial cells, which begin to express steroidogenic enzymes early in development. Studies suggest that neurosteroids may play important roles in neuronal circuit maturation via autocrine and/or paracrine actions. However, the mechanism of action of these agents is not fully understood. We report here that the excitatory neurosteroid pregnenolone sulfate induces a long-lasting strengthening of AMPA receptor-mediated synaptic transmission in rat hippocampal neurons during a restricted developmental period. Using the acute hippocampal slice preparation and patch-clamp electrophysiological techniques, we found that pregnenolone sulfate increases the frequency of AMPA-mediated miniature excitatory postsynaptic currents in CA1 pyramidal neurons. This effect could not be observed in slices from rats older than postnatal day 5. The mechanism of action of pregnenolone sulfate involved a short-term increase in the probability of glutamate release, and this effect is likely mediated by presynaptic NMDA receptors containing the NR2D subunit, which is transiently expressed in the hippocampus. The increase in glutamate release triggered a long-term enhancement of AMPA receptor function that requires activation of postsynaptic NMDA receptors containing NR2B subunits. Importantly, synaptic strengthening could also be triggered by postsynaptic neuron depolarization, and an anti-pregnenolone sulfate antibody scavenger blocked this effect. This finding indicates that a pregnenolone sulfate-like neurosteroid is a previously unrecognized retrograde messenger that is released in an activity-dependent manner during development.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pregs Induces a Long-lasting Increase In Mepsc Frequency Durmentioning

confidence: 97%

See 2 more Smart Citations

Neurosteroid-Induced Plasticity of Immature Synapses via Retrograde Modulation of Presynaptic NMDA Receptors

Mameli

Carta²,

Partridge³

et al. 2005

J. Neurosci.

106

122

View full text Add to dashboard Cite

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“…For example, NMDA binding, measured by autoradiography, is decreased in the frontal cortex of ovx rats following administration of progesterone or estradiol benzoate+progesterone (Cyr et al, 2000;Wu et al, 1991). As well, progestins can rapidly alter NMDAR function by increasing or decreasing NMDA-activated calcium influx and blocking progesterone's metabolism to 3α,5α-THP attenuates this effect (Gibbs et al, 1999;Smith, 1991). Progestins also indirectly alter NMDAR function in the hypothalamus and preoptic area by modulating the release of glutamate (Carbone et al, 1995;Fleischmann et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

MK-801 infusions to the ventral tegmental area and ventromedial hypothalamus produce opposite effects on lordosis of hormone-primed rats

Petralia¹,

DeBold²,

Frye³

2007

Pharmacology Biochemistry and Behavior

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Progesterone initiates female sexual behavior of rodents (lordosis) through actions at intracellular progestin receptors in the ventromedial hypothalamus. Progesterone's metabolite, 5α-pregnan-3α-ol-20-one, mediates the intensity and duration of lordosis through its actions at GABA A receptors in the ventral tegmental area. Whether progestins can influence sexual behavior through actions that involve N-methyl-D-aspartate receptors (NMDARs) in the ventromedial hypothalamus and ventral tegmental area was investigated. The current study examines the effect of bilateral ventral tegmental area or ventromedial hypothalamus infusions of the non-competitive NMDAR antagonist (+)-MK-801 hydrogen maleate (MK-801; 0, 20, or 200 ng) on lordosis, motor activity, and NMDA R1 subtype (NMDAR1) immunoreactivity in estradiol benzoate (10 μg)+ progesterone (50 μg)-and estradiol benzoate+vehicle primed rats. Compared to vehicle infusions, infusions of MK-801 to the ventral tegmental area facilitated lordosis of estradiol benzoate (10 μg)+progesterone (50 μg)-and estradiol benzoate+vehicle primed rats. Infusions of MK-801 to the ventromedial hypothalamus inhibited lordosis of estradiol benzoate (10 μg)+progesterone (50 μg)-and estradiol benzoate+vehicle primed rats, compared to vehicle. There was no effect of MK-801 infusions to the ventral tegmental area or the ventromedial hypothalamus on motor behavior. Immunocytochemistry for NMDAR1 revealed MK-801 (200 ng) infusions to the ventral tegmental area or ventromedial hypothalamus of estradiol benzoate (10 μg)+progesterone (50 μg)-or estradiol benzoate+vehicle primed rats significantly reduced the number of darkly stained NMDAR1-immunoreactive cells, compared to vehicle infusions. These data suggest NMDARs may be important in the mediation of hormonal actions in both the ventral tegmental area and the ventromedial hypothalamus for sexual receptivity of rodents, but in different ways.

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