Effect of brain‐derived neurotrophic factor haploinsufficiency on stress‐induced remodeling of hippocampal neurons

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity‐dependent manner, as a mediator of the stress‐induced dendritic remodeling. The analysis of Golgi‐impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF^±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF^± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF^± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. © 2010 Wiley‐Liss, Inc.     

BDNF enhances dendritic Ca2+ signals evoked by coincident EPSPs and back-propagating action potentials in CA1 pyramidal neurons

BDNF, a member of the neurotrophin family, is emerging as a key modulator of synaptic structure and function in the CNS. Due to the critical role of postsynaptic Ca(2+) signals in dendritic development and synaptic plasticity, we tested whether long-term exposure to BDNF affects Ca(2+) elevations evoked by coincident excitatory postsynaptic potentials (EPSPs) and back-propagating action potentials (bAPs) in spiny dendrites of CA1 pyramidal neurons within hippocampal slice cultures. In control neurons, a train of 5 coincident EPSPs and bAPs evoked Ca(2+) elevations in oblique radial branches of the main apical dendrite that were of similar amplitude than those evoked by a train of 5 bAPs alone. On the other hand, dendritic Ca(2+) signals evoked by coincident EPSPs and bAPs were always larger than those triggered by bAPs in CA1 neurons exposed to BDNF for 48 h. This difference was not observed after blockade of NMDA receptors (NMDARs) with D,L-APV, but only in BDNF-treated neurons, suggesting that Ca(2+) signals in oblique radial dendrites include a synaptic NMDAR-dependent component. Co-treatment with the receptor tyrosine kinase inhibitor k-252a prevented the effect of BDNF on coincident dendritic Ca(2+) signals, suggesting the involvement of neurotrophin Trk receptors. These results indicate that long-term exposure to BDNF enhances Ca(2+) signaling during coincident pre- and postsynaptic activity in small spiny dendrites of CA1 pyramidal neurons, representing a potential functional consequence of neurotrophin-mediated dendritic remodeling in developing neurons.     

Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation

The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal-dependent learning and memory is higher in the brains of aged mice compared to young adults after peripheral injection of lipopolysaccharide (LPS). In this study we investigated whether the exaggerated inflammatory cytokine response in the hippocampus of aged mice after IP injection of LPS is associated with architectural changes to dendrites of pyramidal neurons in the dorsal CA1 hippocampus. Compared to young adults, aged mice had higher basal expression of MHC class II, lower basal expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and a decrease in total dendritic length in both the basal and apical tree. After IP LPS administration, expression of IL-1β, IL-6, and TNFα mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72 h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that a peripheral infection in the aged can cause a heightened inflammatory cytokine response in the hippocampus and atrophy of hippocampal neurons. Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.     

Roles of afadin in the formation of the cellular architecture of the mouse hippocampus and dentate gyrus

The hippocampal formation with tightly packed neurons, mainly at the dentate gyrus, CA3, CA2, and CA1 regions, constitutes a one-way neural circuit, which is associated with learning and memory. We previously showed that the cell adhesion molecules nectins and its binding protein afadin play roles in the formation of the mossy fiber synapses which are formed between the mossy fibers of the dentate gyrus granule cells and the dendrites of the CA3 pyramidal cells. We showed here that in the afadin-deficient hippocampal formation, the dentate gyrus granules cells and the CA3, CA2, and CA1 pyramidal cells were abnormally located; the mossy fiber trajectory was abnormally elongated; the CA3 pyramidal cells were abnormally differentiated; and the densities of the presynaptic boutons on the mossy fibers and the apical dendrites of the CA3 pyramidal cells were decreased. These results indicate that afadin plays roles not only in the formation of the mossy fiber synapses but also in the formation of the cellular architecture of the hippocampus and the dentate gyrus.     

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase/nitric oxide synthase profiles in the human hippocampal formation and perirhinal cortex

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-stained profiles were evaluated throughout the human hippocampal formation (i. e., dentate gyrus, Ammon's horn, subicular complex, entorhinal cortex) and perirhinal cortex. NADPH-d staining revealed pleomorphic cells, fibers, and blood vessels. Within the entorhinal and the perirhinal cortices, darkly stained (type 1) NADPH-d pyramidal, fusiform, bipolar, and multipolar neurons with extensive dendrites were scattered mainly within deep layers and subjacent white matter. Moderately stained (type 2) NADPH-d round or oval neurons were seen mainly in layers II and III of the entorhinal and perirhinal cortices, in the dentate gyrus polymorphic layer, in the CA fields stratum pyramidal and radiatum, and in the subicular complex. The distribution of type 2 cells was more abundant in the perirhinal cortex compared to the hippocampal formation. Lightly stained (type 3) NADPH-d pyramidal and oval neurons were distributed in CA4, the entorhinal cortex medial subfields, and the amygdalohippocampal transition area. Sections concurrently stained for NADPH-d and nitric oxide synthase (NOS) revealed that all type 1 neurons coexpressed NOS, whereas types 2 and 3 were NOS immunonegative. NADPH-d fibers were heterogeneously distributed within the different regions examined and were frequently in close apposition to reactive blood vessels. The greatest concentration of fibers was in layers III and V–VI of the entorhinal and perirhinal cortices, dentate gyrus polymorphic and molecular layers, and CA1 and CA4. A band of fibers coursing within CA1 divided into dorsal and ventral bundles to reach the presubiculum and entorhinal cortex, respectively. Although the distribution of NADPH-d fibers was conserved across all ages examined (28–98 years), we observed an increase in the density of fiber staining in the aged cases. These results may be relevant to our understanding of selective vulnerability of neuronal systems within the human hippocampal formation in aging and in neurodegenerative diseases. © 1995 Wiley-Liss, Inc.     

Increased proximal bifurcation of CA1 pyramidal apical dendrites in sema3A mutant mice

Semaphorin‐3A (Sema3A) is an attractive guidance molecule for cortical apical dendrites. To elucidate the role of Sema3A in hippocampal dendritic formation, we examined the Sema3A expression pattern in the perinatal hippocampal formation and analyzed hippocampal dendrites of the brains from young adult sema3A mutant mice. Sema3A protein was predominantly expressed in the hippocampal plate and the inner marginal zone at the initial period of apical dendritic growth. Neuropilin‐1 and plexin‐A, the receptor components for Sema3A, were also localized in the same regions. The Golgi impregnation method revealed that in wildtype mice more than 90% of hippocampal CA1 pyramidal neurons extended a single trunk or apical trunks bifurcated in stratum radiatum. Seven percent of the pyramidal neurons showed proximal bifurcation of apical trunks in stratum pyramidale or at the border of the stratum pyramidale and stratum radiatum. In sema3A mutant mice, proximally bifurcated apical dendrites were increased to 32%, while the single apical dendritic pyramidal neurons were decreased. We designate this phenotype in sema3A mutant mice as “proximal bifurcation.” In the dissociated culture system, approximately half of the hippocampal neurons from wildtype mice resembled pyramidal neurons, which possess a long, thick, and tapered dendrite. In contrast, only 30% of the neurons from sema3A mutants exhibited pyramidal‐like morphology. Proximal bifurcation of CA1 pyramidal neurons was also increased in the mutant mice of p35, an activator of cyclin‐dependent kinase 5 (Cdk5). Thus, Sema3A may facilitate the initial growth of CA1 apical dendrites via the activation of p35/Cdk5, which may in turn signal hippocampal development. J. Comp. Neurol. 516:360–375, 2009. © 2009 Wiley‐Liss, Inc.     

Sensitivity to GABA of the soma and dendrites of pyramidal cells in isolated sections of hippocampus in the rat

The depressing effect of GABA on excitation of nerve cells as well as the action of bicuculline, penicillin and thiopental on this process were examined on CA1 pyramidal neurons using rat hippocampal slices. It was found that GABA effectively and reversibly reduced the amplitude of antidromic population spike both in the region of somata and dendrites. The sensitivity of apical dendrites to GABA was greater by one order than that of somata, increasing along dendrites from their proximal to distal parts. The somata of pyramidal neurons showed strong desensitization to GABA. In distal parts of dendrites desensitization to GABA was absent. Bicuculline and penicillin antagonized the action of GABA at all investigated levels of CA1 pyramidal cells. Bicuculline blocked the effect of GABA on the somata and dendrites approximately equally. The antagonistic action of penicillin was 10 times larger in the pyramidal layer than in the region of dendrites. Thiopental intensified the depression produced by GABA. Potentiating effect of thiopental was stronger in dendrites. It is concluded that the membrane of CA1 pyramidal neurons has two types of bicuculline-sensitive GABA-receptors differing in their location (mainly on the soma or dendrites), in pharmacology and in ability to be desensitized by GABA.     

AMPA-selective glutamate receptor subtype immunoreactivity in the aged human hippocampal formation

It has been hypothesized that, in Alzheimer's disease, glutamate-mediated excitotoxicity contributes to the degeneration of selected populations of neurons. In the present study, immunocytochemical techniques were used to determine the distribution and anatomical features of GluR1- and GluR2/3-immunolabeled cell bodies and processes within the hippocampal formation of normal (i.e., no pathology) elderly humans. The results of this study provide an essential baseline with which to compare the expression and distribution of glutamate receptor subunits within the brains of patients with Alzheimer's disease. With respect to GluR1 immunoreactivity, the molecular layer of the dentate gyrus displays the most intense immunolabeling of any hippocampal structure. Contributing to this intense labeling are apical dendrites that arise from neurons within the adjacent granule cell layer. Interestingly, GluR1-labeled neurons account for a relatively small percentage of the total number of neurons as revealed by Nissl staining in the granule cell layer. In contrast, GluR2/3-labeled neurons are densely distributed throughout the granule cell layer, yet they provide relatively few processes to the adjacent molecular layer compared to GluR1-positive processes. GluRl labeling is also prominent within the CA fields of Ammon's horn, with CA2 > CA3 > CA1 ≥ CA4. Most prominent within the CA fields are the labeled dendrites of pyramidal neurons. In many instances, apical dendrites can be traced into the adjacent stratum radiatum, where they impart a deep striated appearance to this region of the hippocampus. Robust GluR2/3 labeling is also observed within the pyramidal layer of Ammon's horn, with an order of staining intensity similar to that observed for GluRl. However, unlike GluRl labeling, which is localized predominantly along dendrites, GluR2/3 labeling is observed primarily in association with ceh bodies. Collectively, these data suggest that the molecular composition of the AMPA receptor complex may differ between the dendrite and soma of granule and pyramidal neurons within the hippocampal formation, so functionally we may predict that these two regions of the neuron would respond differently following glutamate receptor stimulation. © 1995 Wiley-Liss, Inc.     

Calcium-Sensitive Translocation of Calmodulin and Neurogranin between Soma and Dendrites of Mouse Hippocampal CA1 Neurons

Calmodulin (CaM) and neurogranin (Ng) are two abundant neuronal proteins whose interactions are implicated in the regulation of synaptic responses and plasticity. We employed the "low-calcium" model of epilepsy in hippocampal slices to investigate the mobilization of these two proteins in CA1 pyramidal neurons. Perfusion of mouse hippocampal slices with Ca(2+)-free artificial CSF (ACSF) caused a suppression of synaptic transmission and generation of epileptic activity; these responses could be reversed by normal Ca(2+)-containing ACSF. Fluorescence immunochemical staining of control hippocampal slices bathed in normal ACSF revealed that CaM and Ng were more concentrated in soma than in dendrites; especially for CaM, it was concentrated in the nucleus. Perfusion of hippocampal slices with Ca(2+)-free ACSF caused translocation of these two proteins from soma to dendrites, and this trafficking was also reversed by Ca(2+)-containing buffer. A reduction of ～15 and 40 nM intracellular Ca(2+), [Ca(2+)](i), caused half-maximum translocation of Ng and CaM, respectively. Hippocampal CA1 pyramidal neurons were the most responsive to this Ca(2+)-sensitive translocation as compared to those from other areas of the hippocampus. These results illustrated the unique feature of hippocampal CA1 pyramidal neurons in sequestering high concentrations of CaM and Ng in soma and releasing them to distal dendrites at reducing level of [Ca(2+)](i).     

Calretinin immunoreactive structures in the human hippocampal formation

The calcium-binding protein calretinin is present in an intrinsic GABAergic and an extrinsic non-GABAergic system in the rat and monkey hippocampal formation. Important species differences have been noted in hippocampal cell types immunostained for calretinin and the termination pattern of calretinin containing hypothalamic afferents in the hippocampus. In the present study, calretinin-containing neurons were visualized using immunocytochemistry in the human hippocampal formation of individuals which showed no significant neuropathological alterations. Calretinin-immunoreactivity was present exclusively in non-granule cells of the dentate gyrus and in non-pyramidal cells of Ammon's horn. Calretinin-positive neurons were found most frequently in the hilus of the fascia dentata and in strate radiatum and lacunosum-moleculare of CA1, whereas neurons in CA2 and CA3 were rarely immunostained. The majority of calretinin-immunoreactive neurons were small, bipolar or fusiform neurons. The dendritic trees of the calretinin-positive neurons were, for the most part, parallel to the dendrites of the principal cells. In the hilus, however, we observed cells with dendrites restricted to the hilar area. These dendrites were parallel to the granule cell layer. In the stratum lacunosum-moleculare, neurons with dendrites oriented parallel to the hippocampal fissure were frequently detected. In general, dendrites were smooth or sparsely spiny, displaying small conventional spines. The axons usually emerged from the proximal dendrite and could be followed over long distances. Axons were thin, had small varicosities and displayed only few collaterals which branched relatively far away from the cell body. Distinct bands of darkly stained calretinin-positive fibers occupied the innermost portion of the dentate molecular layer and the pyramidal cell layer of CA2. This distribution of calretinin-immunoreactive structures in the human hippocampus is similar to that observed in other primates but differs from that described in lower mammals, i.e., the rat. Our findings suggest that primates may share a common hippocampal calrtinin-containing system, presumably both the intrinsic GABAergic and the extrinsic hypothalamic non-GABAergic components. © 1995 Wiley-Liss, Inc.     

Perisomatic granules (non-plaque dystrophic dendrites) of hippocampal CA1 neurons in Alzheimer's disease and Pick's disease: a lesion distinct from granulovacuolar degeneration

A number of pathological changes have been reported in relation to CA1 pyramidal cells in Alzheimer's disease (AD), among them hyperphosphorylation of tau protein followed by the formation of filamentous tau lesions, granulovacuolar degeneration (GVD), Hirano bodies and spindle-shaped dilatations of distal apical dendrites. Juxtacellular clusters of glutamate receptor (GluR)-positive granules around pyramidal cells of the CA1 sector have been recently reported under the term "non-plaque dystrophic dendrites". We independently found that CA1 pyramidal cells in AD patients are regularly surrounded by ubiquitin-positive granules measuring 1-4 microns in diameter, which we have termed perisomatic granules (PSG). Using confocal microscopy, ubiquitin- and GluR-reactive granules were found to largely coincide and to correspond to the same structure. By immunoelectron microscopy PSG were found to consist of GluR1-2-reactive enlarged synaptic boutons containing tubulo-filamentous or floccular material. PSG were found to be consistently associated with pyramidal (principal) cells but not with interneurons of the CA1 sector. Dual-labeling experiments have shown that PSG are preferentially associated with tau-immunoreactive "pretangle" neurons but not with cells containing filamentous tau inclusions or with tau-negative nerve cell bodies. The number of PSG was found to increase with the severity of AD changes with almost no PSG found in Braak stages I and II and few in stage III. Furthermore, PSG were not AD specific, as shown by their presence around CA1 pyramidal cells in Pick's disease. The reasons for GluR reactivity and ubiquitin complex formation in enlarged perisomatic boutons are unclear. Marked changes in GluR subunits have been observed in association with even moderate AD pathology in hippocampal pyramidal cells in AD and our findings suggest a pathogenic link between PSG and early tau pathology in CA1 neurons. PSG might represent residual and abnormally clustered GluR subunits in degenerating perisomatic neurites. Our work confirms and extend previous study on perisomatic "non-plaque dystrophic dendrites" in AD and establish PSG as a pathological entity distinct from GVD. In addition PSG should be acknowledged among main histological changes associated with hippocampal neurons in AD and Pick's disease.     

Regional and laminar specificity of kainate-stimulated cobalt uptake in the rat hippocampal formation

Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors were initially found to be impermeable to calcium, but cloning and expression studies subsequently revealed that certain kainate and AMPA receptor subunit combinations display substantial divalent cation permeability. The regional and cellular distribution of calcium-permeable kainate/AMPA receptors has not been extensively investigated, however. In this study, we used a histochemical technique, the kainate-stimulated cobalt uptake assay, to localize calcium-permeable kainate responsive receptors in the rat hippocampal formation. In the presence of cobalt, kainate produced a highly localized, dark granular precipitate in dendrites, perikarya, or both, of hippocampal neurons. Kainate-stimulated cobalt uptake was time- and concentration-dependent (1 μM–1 mM) and was blocked by the glutamate receptor antagonist, kynurenate. The specific cellular location of cobalt labeling varied regionally within the hippocampal formation, switching from selective labeling of only apical dendrites in Ammon's horn subregion 1a (CA1a) to a diffuse band of punctate labeling in CA1c to labeling of cell bodies along with their proximal dendrites in CA3. Furthermore, increasing the kainate concentration not only enhanced the intensity of cobalt labeling, but also changed the pattern of cellular staining from exclusively dendritic labeling to extensive staining of both cell bodies and dendrites in CA1a pyramidal neurons. High kainate concentrations or prolonged incubation times produced a diffuse cellular labeling suggestive of neurotoxicity. These data are consistent with evidence that specific kainate and AMPA receptor subunit combinations are targeted to specific synapses in hippocampal pyramidal neurons. J. Comp. Neurol. 402:141–154, 1998. © 1998 Wiley-Liss, Inc.     

Protein kinase C subspecies distinguish major cell types in rat hippocampus: an immunocytochemical and in situ hybridization histochemical study.

This study compares the distribution of protein kinase C (PKC) alpha and beta with the distribution of PKC epsilon in the hippocampal formation of rats by immunocytochemistry and in situ hybridization histochemistry. Alpha and PKC beta are members of the group A PKC genes that were first described; PKC epsilon is a member of the group B PKC genes that were more recently identified by molecular cloning. A combination of all three gene products and their mRNAs overlapped in their distributions in dentate granule cells and pyramidal and nonpyramidal neurons. However, each subspecies predominated in one of the major cell types. PKC alpha-immunoreactivity and mRNA were most intense in CA2-3 pyramidal cells and dendrites, whereas PKC beta-immunoreactivity and mRNA were most intense in CA1 pyramidal cells and dendrites. PKC epsilon-immunoreactivity and mRNA were concentrated in dentate granule cells and CA3 pyramidal cells. Furthermore, PKC epsilon-immunoreactivity was detectable in mossy fibers. Each subspecies labeled different kinds of interneurons that were particularly numerous in, but not restricted to, the hilus. These data support the contention that different subtypes of hippocampal neurons are distinguished by the expression of different combinations of PKC subspecies under resting conditions.     

A light and electron microscopic study of the metabotropic glutamate receptor mGluR1a in the normal and kainate-lesioned rat hippocampus

The distribution of the metabotropic glutamate receptor mGluR1a was studied in the normal and kainate-lesioned rat hippocampus using a monoclonal (MAb) and a polyclonal antibody to mGluR1a. Many labeled nonpyramidal neurons were observed in the stratum oriens of CA1 in sections incubated with MAb. In comparison, fewer labeled neurons were observed in this layer in sections incubated with polyclonal antibody. Many nonpyramidal neurons were observed in the stratum lucidum of CA3 and the hilus of the dentate gyrus, with both antibodies. The cell bodies of pyramidal neurons were unlabeled. A dense network of labeled processes was observed in the neuropil of the CA fields at electron microscopy. Some dendrites were very densely labeled and did not contain dendritic spines. These were identified as dendrites of nonpyramidal neurons. Other dendrites contained lightly labeled dendritic shafts, but densely labeled dendritic spines, and were identified as dendrites of pyramidal neurons. Intravenous kainate injections resulted in destruction of pyramidal neurons and a massive decrease in mGluR1a immunoreactivity in the CA fields. This decrease was obvious even at 1–5 d postinjection, when the nonpyramidal neurons in the stratum oriens remained densely labeled, suggesting that pyramidal neurons contributed significantly to mGluR1a staining in the CA fields. We conclude that the dendritic spines of hippocampal pyramidal neurons contain mGluR1a, even though little staining is observed in their parent dendritic shafts or cell bodies.     

Serotonin receptor 1A modulates actin dynamics and restricts dendritic growth in hippocampal neurons

Mice lacking serotonin receptor 1A (Htr1a) display increased anxiety behavior that depends on the expression of the receptor in the forebrain during the third to fifth postnatal weeks. Within the forebrain, Htr1a is prominently expressed in the soma and dendrites of CA1 pyramidal neurons of the hippocampus and these cells undergo rapid dendritic growth and synapse formation during this period. Consistent with a possible role of Htr1a in synaptic maturation, CA1 pyramidal neurons in the knockout mice show increased ramification of oblique dendrites. These findings suggest that Htr1a may shape hippocampal circuits by directly modulating dendritic growth. Here we show that pharmacological blockade of the receptor during the third to fifth postnatal weeks is sufficient to reproduce the increased branching of oblique dendrites seen in knockout mice. Using dissociated hippocampal cultures we demonstrate that serotonin functions through Htr1a to attenuate the motility of dendritic growth cones, reduce their content of filamentous actin and alter their morphology. These findings suggest that serotonin modulates actin cytoskeletal dynamics in hippocampal neurons during a limited developmental period to restrict dendritic growth and achieve a long‐term adjustment of neural connectivity.     

Kainate-induced zinc translocation from presynaptic terminals causes neuronal and astroglial cell death and mRNA loss of BDNF receptors in the hippocampal formation and amygdala

To evaluate the potential role of endogenous zinc in the pathophysiology of epilepsy, we injected kainic acid into the medial septum, which evokes seizure activity and delayed hippocampal degeneration. Different approaches were used. In the hippocampus, we found a movement of zinc from the synaptic compartment to CA1 pyramidal neurons and astrocytes after kainate. The same was true in the amygdala. We found that in those areas showing intense zinc bleaching there was also a loss of reactive astrocytes, which supports the view that release of synaptic zinc induces astrocytic cell death. We have also tested whether the kainate-induced zinc movement from the synaptic compartment to neuronal or glial cells alters the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, trkB. There was a prominent loss of expression of trkB mRNA in areas that coincided precisely with those displaying astrocyte loss and zinc bleaching. In the amygdala, these events were accompanied by a high upregulation of BDNF mRNA. To demonstrate further a role of synaptic zinc in hippocampal pathology, we used two different approaches. We first injected different doses of zinc chloride in the CA1 area. At lower doses (0.1-10 nmol), zinc chloride selectively induced apoptosis in CA1 pyramidal neurons and dentate granular neurons. In a second approach, we found that hippocampal zinc chelation was effective in protecting CA1 pyramidal neurons against kainate-induced cell death.     

Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox

Repeated stress induces atrophy, or remodeling, of apical dendrites in hippocampal CA3 pyramidal neurons. In rats, the stress effect is blocked by adrenal steroid synthesis inhibitors, and mimicked by daily injection of corticosterone. We report that non-invasive administration of corticosterone in the drinking water (400 μg/ml) also produced atrophy of apical dendrites in CA3. Unexpectedly, the combination of daily stress and oral corticosterone negated the effects of either treatment alone, and no changes in the apical dendritic length or branching pattern of CA3 pyramidal neurons were observed compared to control unstressed rats.     

Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.

The levels of brain-derived neurotrophic factor (BDNF) vary between different forebrain areas and show region-specific changes after cerebral ischemia. The present study explores the possibility that the levels of endogenous BDNF determine the susceptibility to ischemic neuronal death. To block BDNF activity the authors used the TrkB-Fc fusion protein, which was infused intraventricularly in rats during 1 week before and 1 week after 5 or 30 minutes of global forebrain ischemia. Ischemic damage was quantified in the striatum and hippocampal formation after 1 week of reperfusion using immunocytochemistry and stereological procedures. After the 30-minute insult, there was a significantly lower number of surviving CA4 pyramidal neurons, neuropeptide Y-immunoreactive dentate hilar neurons, and choline acetyltransferase- and TrkA-positive, cholinergic striatal interneurons in the TrkB-Fc-infused rats as compared to controls. In contrast, the TrkB-Fc treatment did not influence survival of CA1 or CA3 pyramidal neurons or striatal projection neurons. Also, after the mild ischemic insult (5 minutes), neuronal death in the CA1 region was similar in the TrkB-Fc-treated and control groups. These results indicate that endogenous BDNF can protect certain neuronal populations against ischemic damage. It is conceivable, though, that efficient neuroprotection after brain insults is dependent not only on this factor but on the concerted action of a large number of neurotrophic molecules.