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W Hesen

Publications and source records attributed to W Hesen.

16 recordsLinked to original sources
PubMed1998

Synaptic transmission in the rat dentate gyrus after adrenalectomy.

Granule cells in the rat hippocampal dentate gyrus contain intracellular receptors for the adrenal hormone corticosterone. Activation of these receptors seems essential for granule cell viability, since removal of the adrenal gland (adrenalectomy) results within three days in apoptotic-like degeneration of granule cells. In the present study we used extracellular in vitro recording methods to study the synaptic transmission in the dentate gyrus of adrenalectomized animals, in sham-operated controls and adrenalectomized rats treated with a low dose of corticosterone. We found that particularly three days after adrenalectomy orthodromic field responses in the dentate gyrus were reduced in amplitude. Corticosterone-treated rats did not show this impairment of synaptic transmission. Antidromically-evoked field responses were also reduced after adrenalectomy, which indicates that postsynaptic cell properties rather than signal transduction in the synapses are under steroid control. Responses to paired pulse stimulation were only marginally affected, suggesting that interneuronal networks may be less affected by the hormones than the principal cells. These electrophysiological data indicate that adrenalectomy induced apoptotic-like degeneration in the hippocampal dentate gyrus is clearly associated with impaired processing of incoming information.

Adrenalectomy↗
PubMed1998

Serotonin and carbachol induced suppression of synaptic excitability in rat CA1 hippocampal area: effects of corticosteroid receptor activation.

Serotonin (5HT) and the cholinergic analogue carbachol (CCh) act on neurons in the hippocampal CA1 area through pre- and post-synaptic receptors. Previously, it was shown that post-synaptic actions of 5HT and CCh are affected by corticosteroids: predominant activation of high affinity mineralocorticoid receptors resulted in small hyperpolarizing responses to 5HT and small depolarizing responses to CCh; additional activation of low affinity glucocorticoid receptors led to increased 5HT and CCh responses. In the present study, we examined the consequences of steroid modulation of these post-synaptic membrane effects and/or possible pre-synaptic effects by 5HT and CCh for the excitability in the CA1 area, using extracellular field potential or intracellular recordings from individual pyramidal neurons. Steroid treatment by itself did not affect the amplitude or paired pulse properties of synaptic responses. In slices from adrenally intact rats, both 5HT (3-30 microM) and CCh (1-10 microM) induced a dose-dependent suppression of the synaptic field responses evoked in the CA1 area by stimulation of the Schaffer collaterals. No changes in these transmitter effects were observed after adrenalectomy. The 5HT induced suppression of the population spike amplitude was, however, reduced after selective occupation of mineralocorticoid receptors. Intracellularly, no significant steroid dependent modulation of (pre-synaptic) 5HT evoked changes in synaptic responses was observed. These data suggest that the steroids modulate post-synaptic but not pre-synaptic 5HT effects and that this modulation is reflected in the excitability of the CA1 region. The CCh induced suppression of the population spike was not affected by corticosteroid receptor activation, indicating that the previously found steroid modulation of post-synaptic CCh effects has no clear consequences for the CA1 excitability.

Adrenal Cortex Hormones↗
PubMed1998

Serotonin and carbachol induced suppression of synaptic responses in rat CA1 hippocampal area: effects of corticosteroid receptor activation in vivo.

Previous studies have shown that corticosteroids affect the changes in membrane potential evoked in CA1 hippocampal neurons by serotonin and the metabolically stable cholinergic analogue carbachol: Low corticosteroid levels induced by steroid administration to adrenalectomized rats or obtained in adrenally intact rats were associated with small transmitter responses. High corticosteroid levels induced by exogenous corticosteroid application or by an acute stress in adrenally intact rats generally evoked large transmitter responses. In the present study we investigated the consequences of this steroid modulation for the main stream of synaptic information in the CA1 hippocampal region, which is carried by amino acids. To this purpose the effect of serotonin and carbachol administration on both extracellularly and intracellularly recorded synaptic responses to Schaffer collateral stimulation were investigated. The data show that the effect of in vivo activation of corticosteroid receptors on the serotonin-induced hyperpolarization of the membrane responses is clearly reflected in the inhibitory effect of serotonin on synaptic responsiveness in the CA1 area. Low circulating levels of corticosterone or selective mineralocorticoid receptor activation reduced the serotonin mediated inhibition of synaptically evoked responses, whereas high corticosterone levels were associated with strong serotonin mediated suppression of synaptic responses. This steroid modulation seems to be specifically aimed at serotonin neurotransmission, as the cholinergic effects on excitatory synaptic transmission were not affected by the hormone treatment.

Adrenalectomy↗
PubMed1997

Corticosteroid effects on electrical properties of brain cells: temporal aspects and role of antiglucocorticoids.

Pyramidal cells in the CA1 hippocampal area express both mineralo- and glucocorticoid receptors (MRs and GRs respectively) to which the rat adrenal hormone corticosterone binds effectively. Through activation of these receptors corticosteroids exert a delayed and persistent control over signal transduction in the hippocampus. Many cellular responses are affected by the hormone, including responsiveness to serotonin (5HT) and the cholinergic agent carbachol (CCh). It was found that predominant MR occupation results within hours in small responses to 5HT and to CCh. Concomitant activation of GRs leads to larger transmitter responses. Particularly strong responses to 5HT were observed 1-4 hours after an acute stress; this could be prevented by pretreatment with the antiglucocorticoid RU38486. Steroids also exert a long-term effect on aminergic responses. Chronic exposure to a very high corticosterone dose was found to depress 5HT responses. These data indicate that short-term fluctuations in corticosterone level alter neurotransmitter responses in the hippocampus, a structure involved in mood and cognition. In addition, long-term aberrations in corticosteroid levels, e.g. due to glucocorticoid feedback resistance in association with several stress-related disorders, also change the hippocampal responsiveness to monoamines. Future studies will have to examine the potential of antiglucocorticoids to restore this disturbed neurotransmitter function.

Adrenal Cortex Hormones↗
PubMed1996

Hippocampal cell responses in mice with a targeted glucocorticoid receptor gene disruption.

Previous studies in rats have shown that cellular properties of hippocampal CA1 neurons are under coordinative control of mineralocorticoid and glucocorticoid receptors (MRs and GRs, respectively). In the present study, we examined electrical properties under conditions of exclusive MR occupation, by using mice with a genetic defect in GRs obtained by homologous recombination techniques. It appeared that in the animals homozygous for the genetic defect, the properties studied, i.e., the voltage-gated Ca currents and responses to serotonin and the cholinergic analog carbachol, resembled the effects observed in adrenalectomized mice, i.e., when no steroid receptors are activated. This may point to the necessity of functional GRs for the development of MR-induced actions. Ca current amplitude and transmitter responses in the heterozygous animals, which combine a reduced amount of GRs in the hippocampus with relatively high circulating levels of corticosterone, were large compared with those in the wild-type controls; this resembles the responses that were observed previously in rats subjected to a very high dose of corticosterone. These findings exemplify the use of GR knockout mice for the study of cellular properties in the brain. Further substantiation of the observations, however, awaits the development of site-specific, inducible GR knockouts.

Animals↗
PubMed1996

Modulation of 5HT1A responsiveness in CA1 pyramidal neurons by in vivo activation of corticosteroid receptors.

In this study we describe modulatory effects exerted by in vivo activation of corticosteroid receptors on 5HT responsiveness of rat CA1 pyramidal neurons. In the first series of experiments, adrenalectomized (ADX) rats were injected with corticosterone one hour prior to decapitation (1-1000 micrograms/100 g body weight) after which 5HT1A induced hyperpolarizations were determined in vitro by means of intracellular recordings. It appeared that 5HT responsiveness was dose-dependently affected by corticosterone injections: 5HT responses were relatively large when no corticosteroid receptors were activated (ADX); similar 5HT responses were observed or when both mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) were occupied by injection of high doses of corticosterone (100-1000 micrograms/100 g body weight). However, compared to the latter group, 5HT hyperpolarizations were significantly suppressed in slices from rats that received moderate amounts of corticosterone (10-30 micrograms/100 g). Next, we investigated whether physiological variations of plasma corticosterone levels as occurring in intact rats correlated with the transmitter responsiveness. It was found that high plasma levels of corticosterone due to either stress or exogenous application of high doses of corticosterone correlated with large 5HT-responses in vitro. Interestingly, the large 5HT responses recorded after stress were clearly suppressed by pretreatment with RU38486, a GR antagonist. Altogether, this study presents further evidence that 5HT transmission in hippocampal CA1 area is modulated by differential steroid receptor activation as may occur under physiological circumstances due to different plasma concentrations of corticosterone.

Adrenalectomy↗
PubMed1996

Cholinergic Responsiveness of Rat CA1 Hippocampal Neurons In Vitro: Modulation by Corticosterone and Stress.

Corticosterone can activate two corticosteroid receptor types in rat hippocampus: low doses activate mineralocorticoid receptors (MR) while high doses additionally activate glucocorticoid receptors (GR). We found that corticosterone, administered to adrenalectomized rats in vivo, dose-dependently modulates carbachol responsiveness of CA1 hippocampal neurons, recorded subsequently in vitro. Thus, the carbachol (3 µM) induced membrane depolarization in CA1 neurons was relatively large in hippocampal slices where either (almost) no corticosteroid receptors were activated (0-1 µg corticosterone/100g body weight) or where both MRs and GRs were occupied by high corticosterone doses (100-1000 µg/100g). Slices from rats that received intermediate doses of corticosterone (10-30 µg/100g) resulting in predominant MR occupation, displayed significantly suppressed carbachol responses. In adrenally intact rats with MRs and GRs fully activated by a very high dose of corticosterone (1 mg/100g), carbachol responses were increased compared to rats that received only the vehicle or that were untreated. When endogenous corticosterone levels were elevated by ether stress, carbachol responses were not increased. These findings suggest that a shift in the relative occupation of MRs and GRs occurring under physiological conditions is associated with modulation of acetylcholine sensitivity in CA1 neurons. After stress, however, the sensitivity to acetylcholine is rather low, although MRs and GRs are fully activated by endogenous corticosterone; this may point to the involvement of additional stress-induced factors modulating the cholinergic responses.

Journal Article↗
PubMed1995

Corticosteroid-mediated modulation of carbachol responsiveness in CA1 pyramidal neurons: a voltage clamp analysis.

Pyramidal neurons in the rat hippocampal CA1 area contain mineralocorticoid (MRs) and glucocorticoid (GRs) receptors for corticosterone. Previous current clamp experiments showed that depolarizations evoked by carbachol (1-3 microM) depend on relative MR/GR occupation: carbachol responses are small with predominant MR-activation and larger when both receptor types are occupied. Multiple K-conductances underlie the carbachol-induced depolarization. In the present study we used the single electrode voltage clamp technique to examine which K-conductances modulated by carbachol are sensitive to corticosteroid treatment in vitro. We observed that 1 microM carbachol significantly reduced the IK,Leak while the IM was hardly affected; carbachol effects on the IK,Leak were significantly reduced under conditions of predominant MR activation compared to simultaneous activation of MRs and GRs. With a higher (10 microM) carbachol dose, steroid modulation of the IK,Leak showed a similar tendency. The amplitude of the IM was largely reduced by 10 microM carbachol but appeared to be not affected by steroid treatment. We conclude that the previously described suppression of the carbachol-induced depolarization with predominant activation MRs is caused by an attenuation of the carbachol action on the IK,Leak.

Adrenal Cortex Hormones↗
PubMed1995

Long-term control of neuronal excitability by corticosteroid hormones.

Hippocampal CA1 neurons express both mineralocorticoid and glucocorticoid receptors. Due to the difference in affinity of the two receptor types for corticosterone and variations in endogenous steroid levels, occupation of the receptors will range between a situation of predominant mineralocorticoid receptor activation and conditions where both receptor types are occupied. It was observed that local signal transduction is regulated by activation of the corticosteroid receptors. Particularly, transmission mediated by biogenic amines appears to be sensitive to steroid control. The data indicate that cholinergic and serotonergic responses are small with predominant mineralocorticoid receptor activation, while additional glucocorticoid receptor activation results in large responses; the reverse has been found for noradrenalin. The steroid-dependent control over transmission by biogenic amines will influence local excitability and therefore functional processes in which the hippocampal system is involved.

Acetylcholine↗
PubMed1994

Steroids and electrical activity in the brain.

Corticosteroid hormones can enter the brain and bind to two receptor subtypes: the high affinity mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) with approximately 10-fold lower affinity. Under physiological conditions the degree of receptor occupation will range from a predominant MR occupation (at the beginning of the inactive period, under rest) to concurrent activation of MRs and GRs (at the circadian peak and after stress). With in vitro electrophysiological recording techniques we observed that neuronal excitability in the CA1 hippocampal field is under a long-term control of MR- and GR-mediated events. The predominant occupation of MRs is associated with a stable amino acid-carried synaptic transmission; calcium- and potassium-currents are small, as are the responses to biogenic amines. Occupation of GRs in addition to MRs results in a gradual failure of CA1 neurons to respond to repeated stimulation of amino acid-mediated input; ionic conductances and responses to biogenic amines are large. In general, electrical properties recorded when both MRs and GRs are unoccupied (i.e. after adrenalectomy) resemble the responses observed when both receptor types are activated. The corticosterone dependency of electrical properties is thus U-shaped. We conclude that MR occupation may be responsible for the maintenance of information processing in the CA1 field and the stability of the circuit. Additional activation of GRs will initially suppress synaptic activity, but may eventually result in an increased instability and even vulnerability of the neuronal networks.

Adrenal Cortex Hormones↗
PubMed1993

Modulation of carbachol responsiveness in rat CA1 pyramidal neurons by corticosteroid hormones.

Pyramidal neurons in the rat CA1 hippocampal area contain membrane receptors for acetylcholine but also intracellular receptors for the adrenal corticosteroid hormone corticosterone, i.e., mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). In this in vitro study we investigated if occupation of MRs or GRs affects the responsiveness of CA1 pyramidal neurons to the cholinergic analogue carbachol. In slices from adrenally intact rats, where probably most of the MRs and a considerable degree of the GRs were occupied, carbachol (0.1-30 microM) induced a dose-dependent: (i) depolarization; (ii) reduction of the afterhyperpolarization and spike frequency accommodation associated with depolarizing current pulses; and (iii) reduction of the synaptically evoked EPSP, slow IPSP and (with higher doses) the fast IPSP. The carbachol responses in slices from adrenalectomized (ADX) rats, where both MRs and GRs are unoccupied, were generally similar to the responses in the adrenally intact controls. However, neurons recorded in slices from ADX rats 1-4 h after a brief (20 min) application of 3 nM aldosterone, thus predominantly occupying MRs, showed a significant reduction of the carbachol (1 microM) induced depolarization, when compared to the adrenally intact group. By contrast, neurons recorded in ADX slices treated with 30 nM corticosterone, inducing simultaneous activation of MRs and GRs, displayed significantly larger carbachol-evoked depolarizations (1 and 3 microM) than neurons in the three previous experimental groups. Carbachol-induced actions on the afterhyperpolarization, accommodation and synaptically evoked responses did not consistently depend on steroid receptor occupation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Structure and expression of the excision repair gene ERCC6, involved in the human disorder Cockayne's syndrome group B.

The human repair gene ERCC6--a presumed DNA (or RNA) helicase--has recently been found to function specifically in preferential nucleotide excision repair (NER). This NER subpathway is primarily directed towards repair of (the transcribed strand of) active genes. Mutations in the ERCC6 gene are responsible for the human hereditary repair disorder Cockayne's syndrome complementation group B, the most common form of the disease. In this report, the genomic organization and expression of this gene are described. It consists of at least 21 exons, together with the promoter covering a region of 82-90 kb on the genome. Postulated functional domains deduced from the predicted amino acid sequence, including 7 distinct helicase signatures, are--with one exception--encoded on separate exons. Consensus splice donor and acceptor sequences are present at all exon borders with the exception of the unusual splice donor at the end of exon VII. The 'invariable' GT dinucleotide in the consensus (C,A)AG/GTPuAGT is replaced by the exceptional GC. Based on 42 GC splice donor sequences identified by an extensive literature search we found a statistically highly significant better 'overall' match of the surrounding nucleotides to the consensus sequence compared to normal GT-sites. This confirms and extends the observation made recently by Jackson (Nucl. Acids Res., 19, 3795-3798 (1991)) derived from analysis of 26 cases. Analysis of ERCC6 cDNA clones revealed the occurrence of alternative polyadenylation, resulting in the (differential) expression of two mRNA molecules (which are barely detectable on Northern blots) of 5 and 7 kb in length.

Animals↗
PubMed1991

Increased effect of noradrenaline on synaptic responses in rat CA1 hippocampal area after adrenalectomy.

Pyramidal neurons in the rat CA1 hippocampal area contain intracellular receptors for the steroid hormone corticosterone, and membrane associated alpha- and beta-adrenergic receptors. We compared the effect of noradrenaline (NA) on the synaptically evoked CA1 field potential in adrenalectomized (ADX) rats, where corticosteroid receptors are not occupied, with sham-operated controls. It appeared that the increase in the amplitude of the field potential induced by 10 microM NA was more pronounced in slices from ADX rats than in sham operated controls. In vitro application of 30 nM corticosterone (20 min) to slices from ADX rats shifted the NA-evoked increases in synaptic efficacy towards the level of the sham operated rats. The incidence of a secondary population spike after application of NA was increased in slices from ADX rats compared to slices from sham controls or ADX rats treated with corticosterone. Occupation of receptors for corticosterone in the hippocampal CA1 area may therefore potentially lead to suppression of excitability.

Adrenalectomy↗
PubMed1991

Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA1 neurons.

Pyramidal neurons in the rat CA1 hippocampal area contain intracellular mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) to which the adrenal hormone corticosterone can bind with differential affinity. The pyramidal neurons also have high amounts of 5-HT1a receptors, which mediate a membrane hyperpolarization. With intracellular recording in vitro, we found that selective occupation of MRs suppresses the 5-HT-induced hyperpolarization of CA1 pyramidal neurons. The suppression of 5-HT responses was observed 1-4 hr after a brief (20-min) application of the steroids. Binding properties of the 5-HT1a receptor were not significantly affected by in vitro steroid application. Furthermore, responses to the GABAB agonist baclofen were not changed after treatment with MR ligands, implying that the K+ conductance to which both GABAB and 5-HT1a receptors are linked is also no target for the steroid action. The MR-mediated effect on 5-HT responsiveness potentially enhances cellular activity. Because activation of GRs was previously found to suppress norepinephrine-induced excitability in the same neurons, the data support the concept that cellular homeostasis in the hippocampus is under control of corticosterone via coordinative, antagonistic MR- and GR-mediated events.

Animals↗