Biomedical subjects

M Joëls

Publications and source records attributed to M Joëls.

At least 19 recordsLinked to original sources

PubMed2007

Dissociation between apoptosis, neurogenesis, and synaptic potentiation in the dentate gyrus of adrenalectomized rats.

Removal of adrenal hormone corticosterone in rats aged 3-4 months results within 3 days in acceleration of apoptosis and proliferation of newborn cells in the dentate gyrus (DG). A critical question is whether such a shift in the maturity of dentate cells after adrenalectomy (ADX) affects synaptic plasticity. To address this question, male rats were adrenalectomized and synaptic potentiation was recorded in vitro in hippocampal slices, as well as in vivo, in response to high frequency stimulation of the perforant path, 3 days after ADX. At this time-point, cell loss was assessed and proliferation was examined. Based on two independent parameters, bromodeoxyuridine and Ki-67, we found that removal of the adrenal glands increases proliferation rate. This increase in proliferation was, in particular, evident in those animals that displayed substantial cell loss. The accelerated cell-turnover after ADX was accompanied by reduced synaptic potentiation, both when recorded in vitro and in vivo. Corticosterone replacement in vivo (in adrenalectomized animals), at levels that activate the mineralocorticoid receptor, prevented ADX-induced proliferation, apoptosis, and restored synaptic potentiation to control levels. Importantly, corticosterone applied to slices from adrenalectomized rats also normalized synaptic potentiation, despite increased proliferation. This suggests that changes in cell proliferation and apoptotic cell death in the DG are not necessarily key factors determining the efficacy of synaptic potentiation.

Adrenalectomy↗

PubMed2006

The dynamic pattern of glucocorticoid receptor-mediated transcriptional responses in neuronal PC12 cells.

The aim of the current study was (i) to examine the overlap in the pattern of glucocorticoid receptor (GR)-mediated transcriptional responses between different neuronal substrates and (ii) to assess the nature of these responses by differentiating between primary and downstream GR-responsive genes. For this purpose, nerve growth factor-differentiated catecholaminergic PC12 cells were used in which endogenous GRs were activated briefly with a high dose of corticosterone followed by gene expression profiling 1 and 3 h afterwards using Affymetrix GeneChips. The results revealed a strikingly similar temporal pattern to that which was reported previously in hippocampus, with only down-regulated genes 1 h after GR activation and the majority of genes up-regulated 3 h after GR activation. Real-time quantatitive PCR of transcripts in cycloheximide-treated cells showed that all five GR-responsive genes selected from the 1-h time point were primary responsive, whereas all four GR-responsive genes selected from the 3-h time point were downstream responsive. At the level of individual genes, the overlap with the previously generated hippocampal data sets was small, illustrating the cell-type specifity of GR-mediated genomic responses. Finally, we identified a number of interesting genes, such as SWI/SNF, synaptosomal-associated protein 25 and certain Rab proteins which may play a role in the effects of glucocorticoids on catecholaminergic neuronal functioning.

Animals↗

PubMed2006

Acute activation of hippocampal glucocorticoid receptors results in different waves of gene expression throughout time.

Several aspects of hippocampal cell function are influenced by adrenal-secreted glucocorticoids in a delayed, genomic fashion. Previously, we used Serial Analysis of Gene Expression to identify glucocorticoid receptor (GR)-induced transcriptional changes in the hippocampus at a fixed time point. However, because changes in mRNA levels are transient and most likely precede the effects on hippocampal cell function, the aim of the current study was to assess the transcriptional changes in a broader time window by generating a time curve of GR-mediated gene expression changes. Therefore, we used rat hippocampal slices obtained from adrenalectomised rats, substituted in vivo with low corticosterone pellets, predominantly occupying the hippocampal mineralocorticoid receptors. To activate GR, slices were treated in vitro with a high (100 nM) dose of corticosterone and gene expression was profiled 1, 3 and 5 h after GR-activation. Using Affymetrix GeneChips, a striking pattern with different waves of gene expression was observed, shifting from exclusively down-regulated genes 1 h after GR-activation to both up and down regulated genes 3 h after GR-activation. After 5 h, the response was almost back to baseline. Additionally, real-time quantitative polymerase chain reaction was used for validation of a selection of responsive genes including genes involved in neurotransmission and synaptic plasticity such as the corticotropin releasing hormone receptor 1, monoamine oxidase A, LIMK1 and calmodulin 2. This permitted confirmation of GR-responsiveness of 15 out of 18 selected genes. In conclusion, direct activation of GR in hippocampal slices results in transient changes in gene expression. The pattern in which gene expression was modulated suggests that the fast genomic effects of glucocorticoids may be realised via transrepression, preceding a later wave of transactivation. Furthermore, we identified a number of interesting candidate genes which may underlie the glucocorticoid-mediated effects on hippocampal cell function.

Animals↗

PubMed2006

Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosterone-induced reduction of adult hippocampal neurogenesis.

The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression. To better understand its mechanism, we investigated mifepristone's cellular effects, and found that it rapidly reversed a chronic corticosterone-induced reduction of adult neurogenesis in rats. Unlike other antidepressants, mifepristone is particularly potent in a high corticosterone environment. These data indicate that similarly to its clinical efficacy, mifepristone's effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.

Age Factors↗

PubMed2006

Effect of chronic stress and mifepristone treatment on voltage-dependent Ca2+ currents in rat hippocampal dentate gyrus.

Chronic unpredictable stress affects many properties in rat brain. In the dentate gyrus, among other things, increased mRNA expression of the Ca2+ channel alpha1C subunit has been found after 21 days of unpredictable stress in combination with acute corticosterone application (100 nM). In the present study, we examined: (i) whether these changes in expression are accompanied by altered Ca2+ currents in rat dentate granule cells recorded on day 22 and (ii) whether treatment with the glucocorticoid receptor antagonist mifepristone during the last 4 days of the stress protocol normalises the putative stress-induced effects. Three weeks of unpredictable stress did not affect Ca2+ current amplitude in dentate granule cells under basal conditions (i.e. after incubation with vehicle solution). However, the sustained Ca2+ current component (which largely depends on the alpha1C subunit) was significantly increased in amplitude after chronic stress when slices had been treated with corticosterone 1-4 h before recording. These findings suggest that dentate granule cells are exposed to an increased calcium load after exposure to an acute stressor when they have a history of chronic stress, potentially leading to increased vulnerability of the cells. The present results are in line with the molecular data on Ca2+ channel alpha1C subunit expression. A significant three-way interaction between chronic stress, corticosterone application and mifepristone treatment was found, indicating that the combined effect of stress and corticosterone depends on mifepristone cotreatment. Interestingly, current density (defined as total current divided by capacitance) did not differ between the groups. This indicates that the observed changes in Ca2+ current amplitude could be attributable to changes in cell size.

Animals↗

PubMed2006

Blockade of glucocorticoid receptors rapidly restores hippocampal CA1 synaptic plasticity after exposure to chronic stress.

Prolonged exposure to stressful events has been reported to inhibit the ability of hippocampal synapses to increase their synaptic efficacy. Here we tested if these effects could be prevented by blocking activation of glucocorticoid receptors during the last 4 days of the stress paradigm. In order to address this question, animals were exposed to 21 days of variable and inescapable stressors. Handled animals served as controls. During the last 4 days of the stress regime, animals were treated with the glucocorticoid receptor antagonist RU486. We found that 1 day after the last stressor, synaptic plasticity in the CA1 area of hippocampal slices is impaired in chronically stressed animals. Importantly, treating chronically stressed animals with RU486 for 4 days completely prevented this decrease in synaptic potentiation; RU486 treatment of handled controls did not affect potentiation. Treating hippocampal slices from control animals with high levels of corticosterone also impaired synaptic plasticity; this effect was similar for untreated and RU486-treated animals. Treating slices from chronically stressed animals with corticosterone did not further decrease synaptic plasticity. These data indicate that 4 days blockade of the glucocorticoid receptor, during a stress regime, is sufficient to fully restore synaptic plasticity.

Animals↗

PubMed2005

Glucocorticoid receptor activation selectively hampers N-methyl-D-aspartate receptor dependent hippocampal synaptic plasticity in vitro.

Corticosterone and exposure to stressful experiences have been reported to decrease hippocampal synaptic plasticity, in particular when relatively mild stimulation paradigms-presumably activating predominantly N-methyl-d-aspartate receptors-are being used. Using various stimulation paradigms and pharmacological approaches we tested therefore the hypothesis that elevated corticosterone levels, by activating glucocorticoid receptors, predominantly hamper N-methyl-D-aspartate receptor dependent synaptic plasticity in vitro. To address this, mouse hippocampal slices were treated for 20 min with corticosterone (100 nM) or vehicle and synaptic efficacy was examined 1-6 h later. First, we found that primed burst potentiation and synaptic potentiation after 10 Hz stimulation are predominantly N-methyl-D-aspartate receptor dependent, and are significantly suppressed after corticosterone treatment. Second, these latter effects were prevented by treating slices with the glucocorticoid receptor antagonist mifepristone prior to and during corticosterone administration. Third, theta burst potentiation, which was shown to involve activation of both N-methyl-D-aspartate receptors, voltage-dependent calcium channels and possibly other mechanisms, was not affected by corticosterone. However, theta-burst potentiation in the presence of nifedipine-singling out primarily the N-methyl-D-aspartate receptor dependent component-was reduced by corticosterone. These results indicate that corticosterone, via glucocorticoid receptor activation, selectively hampers N-methyl-D-aspartate receptor dependent synaptic plasticity in vitro and leaves more complex forms of long term potentiation unaffected. We speculate that these effects are involved in the impairment of cognitive performance by corticosteroid hormones after exposure to stressful and traumatic experiences.

Animals↗

PubMed2004

Increased P27KIP1 protein expression in the dentate gyrus of chronically stressed rats indicates G1 arrest involvement.

Various chronic stress paradigms decrease new cell proliferation in the hippocampal dentate gyrus, yet the exact underlying mechanism is still unclear. In the first gap (G1) phase of the cell cycle, both stimulatory and inhibitory signals derived from the extracellular environment converge. Corticosteroids, which increase during stress and are well-known anti-mitotics, cause cells in vitro to arrest in the G1 phase. Following 3 weeks of unpredictable stress, we therefore expected a change in protein expression of various important G1 cell cycle regulators in the adult rat subgranular zone. Using quantitative immunocytochemistry, we show that particularly cyclin-dependent kinase inhibitor p27Kip1 expression is significantly increased. In addition, 3 weeks of recovery after stress normalized the numbers of p27Kip1-expressing cells, consistent with the recovered adult cell proliferation in these animals. P27Kip1-positive cells do not overlap with GFAP-staining and only to a limited extent with Ki-67-expressing cells. Numbers of cyclin E- and cyclin D1-expressing cells did not change after chronic stress. These results indicate that chronic stress causes cycling cells in the adult hippocampus to arrest in G1, thereby providing more mechanistic insight in the stress-induced decrease in cell proliferation.

Animals↗

PubMed2004

Gene expression profiles associated with survival of individual rat dentate cells after endogenous corticosteroid deprivation.

Removal of circulating corticosterone by adrenalectomy (ADX) leads to apoptosis after 3 days in a small population of rat dentate granule neurons, whereas most surrounding cells remain viable. Interestingly, a specific expression profile is triggered in surviving granule cells that may enhance their survival. Hippocampal slices prepared 1, 2 or 3 days after ADX or sham operation were stained ex vivo with Hoechst 33258, which serves to identify apoptotic neurons. After electrophysiological analysis, multiple gene expression in surviving individual granule cells was assessed by linear antisense RNA amplification and hybridization to slot blots containing various neuronal cDNAs. Hierarchical clustering and principal component analysis was performed on two physiological variables and 14 mRNA ratios from ADX cells from every time point. Our results indicate that surviving 3-day ADX granule cells display lower membrane capacitance, lower relative N-methyl-d-aspartate (NMDA) R1 mRNA expression and higher relative mineralocorticoid receptor (MR), alpha1A voltage-gated Ca-channel, Bcl-2 and NMDA R2C mRNA expression. Some 1- and 2-day ADX cells cluster with these 3-day survivors; therefore, one or more components of their mRNA expression profile may represent predictive markers for apoptosis resistance. The functional relevance of two candidate genes was tested by in vivo local over-expression in the same model system; of these, Bcl-2 conferred partial protection when induced shortly before ADX. Therefore, removal of corticosteroids triggers a specific gene expression profile in surviving dentate granule cells; key components of this profile may be associated with their survival.

Adrenalectomy↗

PubMed2003

Chronic unpredictable stress causes attenuation of serotonin responses in cornu ammonis 1 pyramidal neurons.

In the present study, serotonin (5-HT) responses of hippocampal pyramidal cornu ammonis 1 (CA1) neurons were studied in rats subjected twice daily for 21 days to unpredictable stressors. In hippocampal tissue from thus stressed rats mRNA expression of the 5-HT(1A) receptor and mineralo- as well as glucocorticoid receptors were examined with in situ hybridization. On average, stressed rats displayed increased adrenal weight and attenuated body weight gain compared with controls, supporting that the animals had experienced increased corticosterone levels due to the stress exposure. One day after the last stressor, under conditions that corticosterone levels were low (predominant mineralocorticoid receptor activation), the 5-HT(1A) receptor mediated hyperpolarization of CA1 neurons in response to 10 microM 5-HT was significantly reduced compared with controls. Basal membrane properties of CA1 cells in stressed rats were comparable to those of controls. The 5-HT(1A) receptor mRNA expression was not changed after chronic stress exposure, in any of the hippocampal areas. A small but significant increase in mineralocorticoid receptor mRNA expression was observed after stress in the dentate gyrus, while glucocorticoid receptor expression was unchanged. The data indicate that unpredictable stress exposure for 3 weeks results in suppression of 5-HT(1A) receptor-mediated responses, possibly due to posttranslational modification of the receptor.

Adrenal Glands↗

PubMed2003

Acute stress increases calcium current amplitude in rat hippocampus: temporal changes in physiology and gene expression.

Activation of hippocampal glucocorticoid receptors in vitro increases calcium current amplitude through a process requiring DNA binding of receptor homodimers. We here investigated (i). whether similar increased calcium currents also occur following in vivo glucocorticoid receptor activation due to stress and (ii). if so, whether this can be explained by increased expression of calcium channel subunits. Rats were exposed to a novelty stress; some of the animals were pretreated with a glucocorticoid receptor antagonist. In subsequently prepared hippocampal slices, calcium currents were recorded from identified CA1 pyramidal neurons, after which RNA was collected, linearly amplified and hybridized with cDNA clones. Glucocorticoid receptor activation due to novelty exposure was associated with large total peak calcium currents and high-threshold noninactivating currents. Low-threshold calcium currents were not affected. Large total peak and noninactivating current amplitudes were also seen when animals received a more severe stressor, i.e. additional ether exposure. In the stressed groups, the total peak and high-threshold calcium current gradually increased with time resulting in a significant enhancement at >or=3 h after stress exposure. In the same cells, the summated (relative) RNA expression of various alpha1 calcium channel subunits was only transiently enhanced, prior to the functional changes. These data indicate that in vivo activation of glucocorticoid receptors due to stress gradually increases specific calcium current components. Prior to the functional change, increased expression of calcium channel subunits was observed, suggesting that the enhanced function could be explained by transcriptional regulation of the channels.

Analysis of Variance↗

PubMed2003

Effect of adrenalectomy on miniature inhibitory postsynaptic currents in the paraventricular nucleus of the hypothalamus.

Within the rat paraventricular nucleus of the hypothalamus two types of neurons have been distinguished based on morphological appearance, i.e., parvocellular and magnocellular neurons. The parvocellular neurons play a key role in regulating the activity of the hypothalamo-pituitary-adrenal axis, which is activated, e.g., after stress exposure. These neurons receive humoral negative feedback via the adrenal hormone corticosterone but also neuronal inhibitory input, either directly or transsynaptically relayed via GABAergic interneurons. In the present study we examined to what extent the neuronal GABAergic input is influenced by the humoral signal. To this end, miniature inhibitory postsynaptic currents (mIPSCs) were recorded in parvo- and magnocellular neurons of adrenalectomized rats, which lack corticosterone, and in sham-operated controls. Under visual control neurons in coronal slices containing the paraventricular nucleus were designated as putative parvocellular or magnocellular neurons: the former were located in the medial part of the nucleus and displayed a small fusiform soma; the latter were mostly located in the lateral part and were recognized by their large round soma. Compared with putative magnocellular neurons, parvocellular neurons generally exhibited a lower membrane capacitance, lower mIPSC frequency, and smaller mIPSC amplitude. Following adrenalectomy, the mIPSC frequency was significantly enhanced in parvo- but not magnocellular neurons. Other properties of the cells were not affected. In a second series of experiments we examined whether the increase in mIPSC frequency was due to the absence of corticosterone or caused by other effects related to adrenalectomy. The data support the former explanation since implantation of a corticosterone releasing pellet after adrenalectomy fully prevented the change in mIPSC frequency. We conclude that, in the absence of humoral negative feedback, local GABAergic input of parvocellular neurons in the paraventricular nucleus is enhanced. This may provide a compensatory mechanism necessary for maintaining controllable network activity.

Adrenal Cortex Hormones↗

PubMed2003

Hippocampal and hypothalamic function after chronic stress.

Hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis is often observed in association with and even prior to the onset of major depression. It is presently unclear (1) which molecular and cellular processes contribute to hyperactivity of parvocellular hypothalamic neurons (key regulators of the HPA system) and (2) how HPA axis hyperactivity can lead to attenuation of central serotonergic transmission, a crucial factor in the onset of clinical symptoms. In an attempt to address these issues in an experimental model we used rats exposed to chronic unpredictable stressors, a paradigm causing prolonged HPA-axis hyperactivity. In the first study spontaneous and evoked GABA-mediated input to parvocellular neurons in the paraventricular hypothalamic nucleus was recorded with the whole cell patch-clamp technique. The frequency, but not other properties, of spontaneous GABA-mediated inhibitory postsynaptic currents was reduced after chronic stress, resulting in a reduced amplitude of the evoked GABA current. This potentially would disinhibit parvocellular neurons, provided that other inputs are unchanged. In the second study, responses of CA1 hippocampal neurons to serotonin were recorded with microelectrodes. It appeared that the membrane hyperpolarization caused by activation of serotonin-1A receptors is attenuated in tissue from chronically stressed rats. However, no apparent changes in expression of the serotonin-1A or corticosteroid receptors were observed. This supports the notion that chronic stress eventually results in attenuation of serotonergic responsiveness by a mechanism not involving transcriptional regulation of the receptor. Follow-up studies will need to examine whether treatment with corticosteroid receptor antagonists can normalize the attenuated transmission after chronic stress.

Animals↗

PubMed2002

Reduced field response to perforant path stimulation after adrenalectomy: effect of nimodipine treatment.

Adrenalectomy enhances apoptosis in the rat dentate gyrus and concurrently decreases the field response of dentate cells to perforant path stimulation. Recent data showed that calcium current amplitude is increased 1 day prior to the appearance of apoptotic cells, pointing to calcium as a risk factor for the onset of apoptosis. We here tested if in vivo administration of nimodipine-thus presumably reducing dentate calcium influx through L type calcium channels-prevents the appearance of apoptotic cells and the change in field responses after adrenalectomy. It was found that nimodipine does not largely alter the number of animals with apoptosis nor the average number of apoptotic cells in the tip of the suprapyramidal blade of the dentate gyrus. After nimodipine treatment, field responses in the dentate gyrus of adrenalectomized rats were comparable to responses in adrenally intact rats. However, this was due to a reduction of the field response in slices from adrenally intact rats, rather than a prevention of synaptic impairment in adrenalectomized rats. The data clearly indicates that in vivo nimodipine treatment is insufficient to prevent apoptosis and synaptic impairment after adrenalectomy.

Animals↗

PubMed2002

Corticosterone and stress reduce synaptic potentiation in mouse hippocampal slices with mild stimulation.

Elevation of circulating corticosterone levels, either through exogenous administration of the hormone or following stress exposure, is known to reduce hippocampal synaptic potentiation in rodents. It is presently debated whether this reduction is due to activation of hippocampal glucocorticoid receptors or is primarily caused in other brain structures projecting to the hippocampus. To address this issue, we examined whether synaptic potentiation in hippocampal slices from mice with low basal corticosterone levels was altered 1-4 h after a brief in vitro administration of 100 nM corticosterone. Population spike and field excitatory postsynaptic potential (fEPSP) were recorded in the cell and dendritic layers, respectively, of the CA1 area, in response to Schaffer collateral/commissural fiber stimulation. Basal characteristics of the stimulus-response relationship were not affected by corticosterone treatment, except that after corticosterone treatment the maximal fEPSP slope was reduced while the excitability ratio was increased. For studies on potentiation of the fEPSP and population spike, stimulus intensities were chosen to evoke half maximal responses before potentiation; this intensity was significantly lower for the fEPSP than for the population spike. Primed burst potentiation of the fEPSP but not population spike was significantly attenuated after corticosterone treatment. When using a more rigorous stimulation paradigm, i.e. theta burst potentiation, synaptic potentiation was not affected by corticosterone. Raising corticosterone levels in mice by exposure to a psychosocial stressor led to comparable results in subsequent in vitro experiments; stress reduced primed burst potentiation only of the fEPSP. These data support that corticosterone affects synaptic potentiation in the mouse via direct activation of hippocampal glucocorticoid receptors but only when using mild stimulation conditions.

Action Potentials↗

PubMed2002

Hippocampal serotonin responses in short and long attack latency mice.

Short and long attack latency mice, which are selected based on their offensive behaviour in a resident-intruder model, differ in their neuroendocrine regulation as well as in aspects of their brain serotonin system. Previous studies showed that the binding capacity and expression of serotonin-1A receptors in the hippocampal CA1 field of long attack latency mice are significantly lower than that found in short attack latency mice. We tested whether the functional responses of CA1 hippocampal cells to serotonin are also reduced in long attack latency mice. To this end, serotonin-induced changes in the membrane potential and input resistance were recorded in vitro with microelectrodes in CA1 pyramidal neurones of long and short attack latency mice. The data show that in long attack latency mice, along with a reduction of the serotonin-1A receptor mRNA expression, the serotonin-induced membrane hyperpolarization and decrease in resistance are attenuated. Basal membrane properties of CA1 neurones in the two.mice lines were comparable. Plasma corticosterone levels in response to a novelty stress were elevated in long compared to short attack latency mice and inversely related to the serotonin-induced responses. We tentatively conclude that long attack latency mice show attenuated functional responses to serotonin in the hippocampus, possibly linked to a chronic perturbation of hormonal levels.

Aggression↗

PubMed2001

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory.

Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired information. The molecular mechanism underlying this phenomenon is entirely unknown. Glucocorticoid receptors can influence transcription both through DNA binding-dependent and -independent mechanisms. To assess the importance of these two modes of action for spatial memory, we here used male mutant mice in which homodimerization and DNA binding of the glucocorticoid receptor is largely prevented (GR(dim/dim)) while protein-protein interactions still can take place. These mice showed a selective impairment of spatial memory in the water maze. Locomotion and anxiety-related parameters measured in an open field and a light/dark preference task were comparable for mutant and control mice. Mutant mice released more corticosterone than control mice under basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-related increase in corticosterone by supplementary injection of corticosterone (250 microg/kg, i.p.) in adrenalectomized mice, resulting in equal plasma corticosterone concentrations in both genotypes, improved spatial memory of control mice but had no effect on mutant mice. These findings suggest that task-related facilitating effects of corticosterone on spatial memory indeed depend on DNA binding of the glucocorticoid receptor rather than on protein-protein interactions of the receptor with other transcription factors. Although it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient to induce impairment.

Animals↗

PubMed2001

Morphological and functional properties of rat dentate granule cells after adrenalectomy.

After complete adrenalectomy, part of the granule cells in the dentate gyrus undergo apoptosis. Findings on morphological changes in non-apoptotic granule cells, though, have been equivocal. In the present study we examined the dendritic trees of dentate granule cells 7 days after adrenalectomy or sham operation, and tested the hypothesis that changes in dendritic trees have considerable consequences for ionic currents, as measured in the soma with whole cell recording. For the latter, we focussed on voltage-gated calcium currents, which are partly generated in distal dendrites. All cells were passively filled with a fluorescent dye via the patch pipette while recording calcium currents; subsequently the cells were three-dimensionally reconstructed with the use of a confocal microscope. In sham-operated rats, dendritic trees of cells with a soma located in the inner part of the granule cell layer (facing the hilus) were significantly smaller than trees of cells located in the outer part of the layer. Neurons from rats that had extremely low (undetectable-0.3 microg/dl) circulating levels of corticosterone displayed very small and simple dendritic trees compared to cells from adrenalectomized rats that still had residual levels of corticosterone (0.6-1.0 microg/dl), regardless of the location of their soma. Despite the observation that simple dendritic trees were seen in rats where corticosterone was extremely low, the whole cell calcium current amplitude recorded from the soma of these cells was not reduced compared to the remaining cells from adrenalectomized or sham-operated rats. Our data indicate that in the absence of corticosterone dendritic trees of dentate granule cells display atrophy but that this does not necessarily reduce ionic currents measured in the soma.

Adrenalectomy↗