Biomedical subjects

Catherine S Woolley

Publications and source records attributed to Catherine S Woolley.

8 recordsLinked to original sources

PubMed2007

Acute effects of estrogen on neuronal physiology.

It has been known for more than 30 years that estrogen can alter the intrinsic and synaptic physiology of neurons within minutes. The physiological significance of these acute effects has been unclear, however, because some effects require higher concentrations of estrogen than are detected in plasma, and because estrogen secreted by the ovary rises and falls over a time course of days, not minutes. These concerns may be answered by new research demonstrating that estrogen is produced at high levels within the brain itself, and that production of estrogen in the brain may be regulated by neuronal activity. Additionally, recent studies indicate that classical estrogen receptor proteins are found not only in the nucleus where they regulate gene expression but also at extranuclear sites, including at synapses. These findings, together with evidence for new types of extranuclear estrogen receptors, suggest that estrogen might act directly at synapses to activate second messenger signaling, thereby rapidly altering neuronal excitability, synaptic transmission, and/or synaptic plasticity.

Electrophysiology↗

PubMed2005

Sexually dimorphic synaptic organization of the medial amygdala.

The medial amygdala is important in social behaviors, many of which differ between males and females. The posterodorsal subnucleus of the medial amygdala (MeApd) is particularly sensitive to gonadal steroid hormones and is a likely site for gonadal hormone regulation of sexually dimorphic social behavior. Here we show that the synaptic organization of the MeApd in the rat is sexually dimorphic and lateralized before puberty. With the use of whole-cell voltage-clamp recording and quantitative electron microscopy, we found that, specifically in the left hemisphere, prepubertal males have approximately 80% more excitatory synapses per MeApd neuron than females. In the left but not the right MeApd, miniature EPSC (mEPSC) frequency was significantly greater in males than in females; mEPSC amplitude was not sexually dimorphic. Paired-pulse facilitation of EPSCs, an index of release probability, also was not sexually dimorphic, suggesting that greater mEPSC frequency is caused by a difference in excitatory synapse number. Electron microscopy confirmed that the asymmetric synapse-to-neuron ratio and the total asymmetric synapse number were significantly greater in the left MeApd of males than of females. In contrast to results for excitatory synapses, we found no evidence of sexual dimorphism or laterality in inhibitory synapses. Neither the frequency nor the amplitude of mIPSCs was sexually dimorphic or lateralized. Likewise, the number of symmetric synapses measured with electron microscopy was not sexually dimorphic. These findings show that the excitatory synaptic organization of the left MeApd is sexually differentiated before puberty, which could provide a sexually dimorphic neural substrate for the effects of hormones on adult social behavior.

Amygdala↗

PubMed2005

Evidence that disinhibition is associated with a decrease in number of vesicles available for release at inhibitory synapses.

We used three-dimensional reconstruction from serial electron micrographs to investigate two structural changes that could underlie estrogen-induced disinhibition of hippocampal CA1 pyramidal cells: a decrease in the number of inhibitory inputs per neuron and/or a change in inhibitory boutons that could limit GABA release. We analyzed 373 boutons forming 510 inhibitory synapses in estrogen-treated and control animals. Our results show that estrogen specifically decreases the number of synaptic vesicles adjacent to the presynaptic membrane of inhibitory synapses without affecting the overall number of vesicles. We detected no difference in the density of inhibitory inputs. These findings provide a novel mechanism for the functional effects of estrogen on synaptic inhibition and represent the first in vivo evidence that the number of presynaptic vesicles available for release is a regulated property of synapses that affects synaptic physiology.

Animals↗

PubMed2005

Gonadal hormone modulation of dendrites in the mammalian CNS.

This review focuses on the effect of gonadal steroid hormones, androgen and estrogen, on dendrites in the adult rat central nervous system (CNS). Four hormone-responsive nuclei are considered: The spinal nucleus of the bulbocavernosus (SNB), the medial nucleus of the amygdala (MeA), the ventromedial nucleus of the hypothalamus (VMN), and the CA1 region of the dorsal hippocampus. Particular emphasis is placed on the mode of hormone action in each nucleus. In the SNB, VMN, and hippocampus, hormones appear to mediate their effects indirectly, via cells other than those that display morphological plasticity. In the MeA, estrogen and/or androgen appears to act primarily on those cells whose dendrites are modulated by the hormone. Importantly, increasing levels of gonadal hormones do not simply result in increases in dendritic parameters. In the VMN, high levels of estrogen associated with proestrus increase dendritic spine density in one subset of cells and reduce spine density in another subset. The pyramidal cells of dorsal CA1 also undergo phasic changes in dendritic spine and synapse density across the estrous cycle. The estrogen-induced excitatory synapses connect with preexisting axonal boutons that also form synapses with other CA1 cells, thereby increasing the divergence of excitatory afferents to dorsal CA1. These findings indicate that gonadal steroids have a profound impact on the morphology of dendrites and patterns of synaptic connectivity. Consequently, the experimental manipulation of hormone levels is a powerful tool to study structure-function relationships in the mammalian brain.

Animals↗

PubMed2004

Maintenance of high-frequency transmission at purkinje to cerebellar nuclear synapses by spillover from boutons with multiple release sites.

Cerebellar Purkinje neurons maintain high firing rates but their synaptic terminals depress only moderately, raising the question of how vesicle depletion is minimized. To identify mechanisms that limit synaptic depression, we evoked 100 Hz trains of GABAergic inhibitory postsynaptic currents (IPSCs) in cerebellar nuclear neurons by stimulating Purkinje axons in mouse brain slices. The paired-pulse ratio (IPSC(2)/IPSC(1)) of the total IPSC was approximately 1 and the steady-state ratio (IPSC(20)/IPSC(1)) was approximately 0.5, suggesting a high response probability of postsynaptic receptors, without an unusually high release probability. Three-dimensional electron microscopic reconstructions of Purkinje boutons revealed multiple active zones without intervening transporters, suggestive of "spillover"-mediated transmission. Simulations of boutons with 10-16 release sites, in which transmitter from any site can reach all receptors opposite the bouton, replicated multiple-pulse depression during normal, high, and low presynaptic Ca influx. These results suggest that release from multiple-site boutons limits depletion-based depression, permitting prolonged, high-frequency inhibition at corticonuclear synapses.

Animals↗

PubMed2004

Cellular and molecular effects of steroid hormones on CNS excitability.

The steroid hormones 17beta-estradiol (estradiol) and progesterone not only regulate the reproductive system but have other central nervous system effects that can directly affect a variety of behaviors. Generally, estradiol has been shown to have activating effects, including the ability to increase seizure activity, while progesterone has been shown to have depressant effects, including anticonvulsant properties. Because levels of these hormones fluctuate across the menstrual cycle, it is important to understand how changes in these hormone levels may influence levels of excitability in the brain, especially in women who have seizure patterns that are related to their menstrual cycle, a phenomenon known as catamenial epilepsy. This paper reviews the effects of estradiol and progesterone on excitatory and inhibitory neurotransmitters, respectively, and the possible cellular and molecular mechanisms underlying the changes in brain excitability mediated by these hormones.

Central Nervous System↗

PubMed2003

A role for the basal forebrain cholinergic system in estrogen-induced disinhibition of hippocampal pyramidal cells.

Estrogen transiently disinhibits hippocampal CA1 pyramidal cells in adult female rats and prolongs the decay time of IPSCs in these cells. Estrogen-induced changes in synaptic inhibition are likely to be causally related to subsequent enhancements in excitatory synaptic function in CA1 pyramidal cells. Currently, it is unknown how or on what cells estrogen acts to regulate synaptic inhibition in the hippocampus. We used whole-cell voltage-clamp recording of synaptically evoked IPSCs, spontaneous IPSCs, and miniature IPSCs in CA1 pyramidal cells to evaluate estrogen-induced changes in synaptic inhibition in ovariectomized rats that either were pretreated with the estrogen receptor (ER) antagonist tamoxifen or in which basal forebrain cholinergic neurons were eliminated by previous infusion of 192IgG-saporin toxin into the medial septum. We found that estrogen-induced disinhibition and prolongation of IPSCs are entirely dependent on a tamoxifen-sensitive ER. Estrogen-induced disinhibition is partially dependent on basal forebrain cholinergic neurons, but the prolongation of IPSCs is not at all dependent on these cells. Paired-pulse experiments and recordings of action potential-related spontaneous IPSCs suggest that estrogen-induced disinhibition is associated with a decrease in probability of release at GABAergic synapses, which decreases the amplitude of IPSCs produced by inhibitory neuron action potentials. Our findings lend novel insights into estrogen regulation of inhibitory synapses in the hippocampus and point to estrogen action on basal forebrain cholinergic neurons as critically involved in mediating the effects of estrogen in the hippocampus.

Action Potentials↗

PubMed2003

Selective estrogen receptor modulators regulate phasic activation of hippocampal CA1 pyramidal cells by estrogen.

Previous studies demonstrated that estrogen induces two sequential waves of CA1 pyramidal cell activation, evidenced by induction of c-Fos at 2 and 24 h after a single estrogen treatment. The second wave of activation is paralleled by suppression of immunoreactivity for glutamic acid decarboxylase-65kD (GAD65) in CA1 and decreased synaptic inhibition of CA1 pyramidal cells. Here, we report that pretreatment with either of the selective estrogen receptor (ER) modulators, tamoxifen (T) or CI628, has no effect on the first wave of c-Fos expression at 2 h but completely blocks the second wave of c-Fos and the suppression of GAD65 at 24 h. Interestingly, T, given 4 h after estrogen, failed to block c-Fos expression or suppression of GAD65 at 24 h. Electrophysiological experiments showed that the T metabolite, 4OH-T, or CI628 can inhibit the so-called rapid estrogen effect, to potentiate excitatory postsynaptic currents (EPSCs) in CA1 pyramidal cells. Thus, estrogen seems to act within 4 h via classical ERs and/or a rapid estrogen effect, such as EPSC potentiation, to produce activation/disinhibition of pyramidal cells 24 h later. In contrast, the initial activation of pyramidal cells, at 2 h after estrogen, seems to involve neither classical ERs nor rapid potentiation of EPSCs.

Animals↗