The multiple aspects of stroke and stem cell therapy.

Cumulative evidence shows that transplantation of stem cells (SC) derivatives can reduce the functional deficits induced by cerebral ischemia or hemorrhage in animals. Most SC sources have been applied to stroke models, with varying degrees of differentiation into neural derivatives and in varying number, timing and route of administration, with similar benefits on functional outcome. Pioneering clinical trials developed in parallel, and currently outnumber other applications of SC in neurological disorders. These trials reflect a paradigm shift from cell replacement therapy to disease-modeling effects, with increased used of non neural SC. This shift stems in experimental demonstration of paracrine effects of SC that attenuate inflammation, limit cell death through neurotrophic effects, and enhance endogenous recovery processes. Due to its pathogenic characteristics, stroke can uniquely benefit from this variety of actions.

NeuroAiD: properties for neuroprotection and neurorepair.

BACKGROUND: Treatments for stroke and other brain injuries are limited. NeuroAiD has been shown to be beneficial in clinical studies. We reviewed the pharmacological effects of NeuroAiD on the normal and ischemic brain and neurons. METHODS: In vivo and in vitro experiments using mouse model of stroke (focal ischemia), rat model of cardiac arrest (global ischemia) and cortical neurons in culture were reviewed and summarized. RESULTS: NeuroAiD improved survival, attenuated infarct size, improved functional recovery in the model of focal ischemia, and protected neurons against glutamate-induced injury. Furthermore, it enhanced cognitive recovery by reducing hippocampal CA1 cell degeneration, DNA fragmentation, Bax expression and ma-londialdehyde release in the model of global ischemia. Activation of the Akt survival pathway and opening of KATP channels may contribute to the neuroprotective properties of NeuroAiD. NeuroAiD increased BDNF expression and induced proliferation of cells which differentiate and mature into neurons. It enhanced rosette formation of human embryonic stem cells. NeuroAiD-treated embryonic cortical neurons developed into neurons with longer neurites, denser outgrowths and networks, and more synaptic release sites. CONCLUSIONS: NeuroAiD demonstrated both neuroprotective and neuroregenerative properties in rodent models of focal and global ischemia and in cortical cell cultures. These properties would be important for developing a treatment strategy in reducing the long-term disability of stroke, cardiac arrest and other brain injuries.

Neuroprotective and neuroproliferative activities of NeuroAid (MLC601, MLC901), a Chinese medicine, in vitro and in vivo.

Although stroke remains a leading cause of death and adult disability, numerous recent failures in clinical stroke trials have led to some pessimism in the field. Interestingly, NeuroAid (MLC601), a traditional medicine, particularly used in China, South East Asia and Middle East has been reported to have beneficial effects in patients, particularly in post-stroke complications. Here, we demonstrate in a rodent model of focal ischemia that NeuroAid II (MLC901) pre- and post-treatments up to 3 h after stroke improve survival, protect the brain from the ischemic injury and drastically decrease functional deficits. MLC601 and MLC901 also prevent neuronal death in an in vitro model of excitotoxicity using primary cultures of cortical neurons exposed to glutamate. In addition, MLC601/MLC901 treatments were shown to induce neurogenesis in rodent and human cells, promote cell proliferation as well as neurite outgrowth and stimulate the development of a dense axonal and dendritic network. MLC601 and MLC901 clearly represent a very interesting strategy for stroke treatment at different stages of the disease.

Specific caspase pathways are activated in the two stages of cerebral infarction.

Necrosis and apoptosis have been initially identified as two exclusive pathways for cell death. In acute brain lesions, such as focal ischemia, this binary scheme is challenged by demonstrations of mixed morphological and biochemical characteristics of both apoptosis and necrosis in single cells. The resulting difficulty in defining the nature of cell death that is triggered by severe insults has dramatically impeded the development of therapeutic strategies. We show that in the early stages of cerebral infarction, neurons of the so-called "necrotic" core display a number of morphological, physiological, and biochemical features of early apoptosis, which include cytoplasmic and nuclear condensations and specific caspase activation cascades. Early activation cascades involve the death receptor pathway linked to caspase-8 and the caspase-1 pathway. They are not associated with alterations of mitochondrial respiration or activation of caspase-9. In contrast, pathways that are activated during the secondary expansion of the lesion in the penumbral area include caspase-9. In agreement with its downstream position in both mitochondria-dependent and -independent pathways, activation of caspase-3 displays a biphasic time course. We suggest that apoptosis is the first commitment to death after acute cerebral ischemia and that the final morphological features observed results from abortion of the process because of severe energy depletion in the core. In contrast, energy-dependent caspase activation cascades are observed in the penumbra in which apoptosis can fully develop because of residual blood supply.

Differential regulation of NGF receptors in primary sensory neurons by adjuvant-induced arthritis in the rat.

In the adult brain, neurotrophins play a key role in adaptive processes linked to increased neuronal activity. A growing body of evidence suggests that chronic pain results from long-term plasticity of central pathways involved in nociception. We have investigated the involvement of nerve growth factor (NGF) in adaptive responses of primary sensory neurons during the course of a long-lasting inflammatory pain model. The amount and distribution of the NGF receptors p75(NTR) and TrkA were measured in the dorsal horn and dorsal root ganglia (DRG) of animals subjected to Freund's adjuvant-induced arthritis (AIA). We observed an increased immunoreactivity of both receptors in the central terminals of primary sensory neurons in the arthritic state. The increases were seen in the same population of afferent terminals in deep dorsal horn laminae. These changes paralleled the variations of clinical and behavioral parameters that characterize the course of the disease. They occurred in NGF-sensitive, but not GDNF-sensitive, nerve terminals. However, p75(NTR) and TrkA protein levels in the DRG (in the cell body of these neurons) showed different response patterns. An immediate rise of p75(NTR) was seen in parallel with the initial inflammation that developed after administration of Freund's adjuvant in hindpaws. In contrast, increases of the mature (gp140(trk)) form of TrkA occurred later and seemed to be linked to the development of the long-lasting inflammatory response. The changes in receptor expression were observed exclusively at lumbar levels, L3-L5, somatotopically appropriate for the inflammation. Together, these results implicate NGF in long-term mechanisms accompanying chronic inflammatory pain, via the up-regulation of its high affinity receptor, and offer additional evidence for differential processes underlying short- versus long-lasting inflammatory pain.

Long-term increase of GluR2 alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunit in the dispersed dentate gyrus after intrahippocampal kainate injection in the mouse.

Intrahippocampal injection of a subtoxic dose of kainate in mice has been shown to induce a dispersion of granule cells of the dentate gyrus, which is a characteristic morphological change often seen in human hippocampal sclerosis. In addition, it has been shown recently that such injections lead to recurrent hippocampal seizures and changes in glucose metabolism, which are reminiscent of temporal lobe epilepsy. Previous reports on human hippocampal sclerosis have shown an increase of the expression of the GluR2 alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate subunits in the dispersed granule cell somata. However, no such changes have been observed so far in animal models of epilepsy with hippocampal sclerosis. In this study, the expression of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunits was examined by immunohistochemistry following intrahippocampal injection of kainate in mice and rats. In mice, such injection induced a persistent increase of GluR2 immunoreactivity in the granule cells for up to 180 days. By contrast, GluR1 immunoreactivity was transiently increased during the first four days after the injection and progressively decreased thereafter. By contrast, intrahippocampal injection of kainate in rats did not result in granule cell dispersion and no changes in GluR1 immunoreactivity or GluR2 immunoreactivity were observed. These results show that, in addition to morphological, clinical and metabolical similarities, intrahippocampal injection of kainate results in a persistent increase of GluR2 associated with granule cell dispersion, as in human hippocampal sclerosis. These data suggest the existence of common mechanisms between granule cell dispersion and regulation of GluR2 subunits associated with hippocampal sclerosis.

Excitatory granule cells of the dentate gyrus exhibit a double inhibitory neurochemical content after intrahippocampal administration of kainate in adult mice.

We have previously demonstrated that, in the adult mouse, injection of kainate/AMPA receptors agonists into the dorsal hippocampus induces major structural modifications of the dentate gyrus granule cells. Such changes are mediated by the brain-derived neurotrophic factor (BDNF). Considering previous involvements of BDNF in activity-linked regulations of hippocampal neuronal phenotype, changes of neurochemical contents were further investigated. It is shown that excitatory granule cells rapidly acquire a strong immunoreactivity for the inhibitory neurotransmitters GABA and neuropeptide-Y, with different patterns for both molecules. GABA immunoreactivity appeared first in mossy fibers, before extending to cell bodies and dendrites. Analysis of glutamic acid decarboxylase revealed slight increases in mossy fibers and no somatic labeling. In contrast to GABA, neuropeptide-Y labeling was observed first in granule cell soma and then in mossy fibers, with a centrifugal gradient. All labelings were transient, but slight amounts of GABA and NPY were kept in some cell bodies for at least 6 months. Confocal microscope analysis of double GABA/NPY labelings revealed colocalization of both mediators in the same neurons. The specificity of kainate-linked changes was suggested by lack of immunoreactivity for somatostatin. These results show that the capacities of mature granule cells to adapt environmental modifications can concern neurochemical contents, by synthesis and/or uptake of specific molecules. The fact that adaptive changes are rapid and transient suggests a direct response to kainate, in order to limit its potentially deleterious effects. Colocalization of GABA and neuropeptide-Y indicates that the dentate gyrus granule cells can use several pathways to this aim.

Reduction of ischemic damage in NGF-transgenic mice: correlation with enhancement of antioxidant enzyme activities.

If permanent focal ischemia is induced by middle cerebral artery occlusion (MCAO), neurons within the infarcted territory die by necrosis and apoptosis (or programmed cell death). We have previously shown, using a mouse strain transgenic (tg) for the nerve growth factor (NGF) gene, that tg mice have consistently smaller infarcted areas than wild-type (wt) animals, correlated with upregulated NGF synthesis and impaired apoptotic cell death. We studied, in wt and tg mice subjected to MCAO, the activities of several antioxidant enzymes and the synthesis of the proteins of the Bcl-2 family. Our results show that the antiapoptotic Bcl-2 protein and glutathione peroxidase are recruited after MCAO. NGF-tg mice also had an intrinsic resistance to oxidative stress because their basal copper zinc superoxide dismutase (SOD) and glutathione transferase activities were high. Additionally, manganese SOD activity increased in NGF-tg mice after MCAO, correlating strongly with the resistance of these mice to apoptosis.

Chronic pain is associated with increased TrkA immunoreactivity in spinoreticular neurons.

Repetitive noxious stimulation leads to permanent adaptive changes of central pathways involved in the genesis and integration of nociception. Several classes of neurotrophic factors that affect brain plasticity are also involved in the regulation of sensory functions in adulthood. To investigate a putative role of nerve growth factor (NGF) in central plasticity linked to chronic pain, modifications in immunoreactivity (IR) for the high-affinity NGF receptor, TrkA, were studied at spinal levels in a rat model of inflammatory chronic pain, adjuvant-induced arthritis (AIA). We report a specific increase in the number of TrkA-IR profiles in laminae V-VI at lumbar levels L3 and L4 in arthritic rats. Tract tracing using FluoroGold injections in the ventrobasal complex of the thalamus and in the brainstem showed that these increased TrkA-IR profiles are spinoreticular neurons. Dual labeling with calcitonin gene-related peptide or substance P showed that TrkA-IR neurons were mainly located in projection fields of small- to medium-sized primary afferent fibers, which convey nociceptive inputs. These results suggest that TrkA-containing neurons of the spinal dorsal horn participate in the first central relay of transmission of nociceptive information to supraspinal centers. Enhanced numbers of TrkA-IR neurons during AIA strongly support the hypothesis of a participation of NGF in adaptive mechanisms of central nociceptive pathways observed in chronic pain states.

BDNF and NT-4 differentiate two pathways in the modulation of neuropeptide protein levels in postnatal hippocampal interneurons.

Neuropeptide protein levels in hippocampal interneurons exhibit a considerable maturation in postnatal animals. This study characterizes the role of neuronal activity in determining neuropeptide protein levels in postnatal hippocampal interneurons, and the involvement of neurotrophins. In hippocampal slices from 7-day-old rats cultured for 2 weeks, treatment with the gamma-aminobutyric acidA (GABAA) receptor antagonist bicuculline increased the staining intensity and the number of neurons immunoreactive for neuropeptide Y (NPY). An opposite effect was observed when non-N-methyl-d-aspartate (non-NMDA) excitatory transmission was blocked. The effects of either treatment were reversed after return to control medium. These findings were similar to those previously obtained on the effects of activity on somatostatin immunostaining. Blockade of endogenous tyrosine kinase neurotrophin receptors using K252a prevented the effects of bicuculline on NPY- and somatostatin-immunoreactive neurons. Application of exogenous neurotrophin-3 (NT-3) increased NPY and somatostatin protein levels in long-term but not short-term cultures, while nerve growth factor (NGF) had no effect. In contrast, brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4) did not affect equally NPY and somatostatin immunoreactivity: they mimicked the effects of bicuculline treatment on NPY-immunoreactive neurons, but exerted no conspicuous effect on somatostatin immunostaining. These results indicate that although neuronal activity plays a major role in determining neuropeptide protein levels in postnatal hippocampal interneurons, its effects on different neuropeptides might be exerted through different mechanisms, with or without the mediation of BDNF or NT-4.

Correlated long-term increase of brain-derived neurotrophic factor and Trk B proteins in enlarged granule cells of mouse hippocampus after kainic acid injection.

Our previous studies have shown that a single injection of kainic acid into the dorsal hippocampus of adult mice resulted in hypertrophy of the dentate gyrus granule cells. This hypertrophy was correlated with a long-lasting increase of brain-derived neurotrophic factor messenger RNA, and prevented by anti-sense brain-derived neurotrophic factor oligonucleotide treatment. These results suggest that an increase of brain-derived neurotrophic factor messenger RNA may be a major trigger of granule cells enlargement. However, the level of messenger RNA of Trk B, the high-affinity receptor of brain-derived neurotrophic factor, was not increased significantly, raising the question of whether increased brain-derived neurotrophic factor messenger RNA level leads actually to an increased protein production. The objective of the present study was to examine this; changes in contents of brain-derived neurotrophic factor and TrkB protein were monitored by immunohistochemistry during kainic acid-induced hypertrophy. Results show that immunoreactivities of brain-derived neurotrophic factor and Trk B were present in enlarged granule cells. These immunoreactivities increased from two to 16 weeks after kainic acid injection and were maintained up to 12 months. Simultaneous increases of brain-derived neurotrophic factor messenger RNA and protein, and of TrkB protein were coupled tightly to the chronology of granule cell enlargement, suggesting that the action of brain-derived neurotrophic factor in the induction and maintenance of kainic acid-induced granule cells enlargement is likely to be mediated by TrkB. The discrepancy between the previously described lack of increase of TrkB messenger RNA and the herein observed increase of the protein further reveals the existence of translational regulations of the receptor messenger RNA.

Reduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice subjected to permanent focal ischemia.

The neuroprotective potential of the nerve growth factor (NGF) against permanent ischemic brain damage has been investigated in vivo using NGF-transgenic (tg) mice. The expression of the transgene is driven by part of the promoter of the proto-oncogene c-fos, which belongs to the first set of genes activated after brain ischemic insult. Wild-type (wt) mice and tg mice were subjected to permanent focal ischemia induced by electrocoagulation of the middle cerebral artery. Twenty four hours (h) after the ischemic shock, when compared to wt, tg mice displayed a 40% reduction of the infarcted area, which lasted up to 1 week. However, infarcted brain areas were similar in wt and tg mice within the first hours post-occlusion, indicating that NGF acted to block the progression of neuronal damage. Kinetics of NGF synthesis assessed by ELISA was in good agreement with the observed neuroprotective effect, since NGF content peaked 6 h post-ischemia. This was further correlated with the time-course of c-Fos immunoreactivity, detectable only from 6 h post-ischemia. The neuroprotective effect of NGF involved the impairment of apoptotic cell death, as evidenced by a marked decrease of the number of apoptotic profiles inside the ischemic zone in tg mice. These results underline the potential of c-fos-NGF-tg mice to study in vivo the molecular and cellular mechanisms of the NGF-induced neuroprotective effect against ischemic damage.

Recruitment of several neuroprotective pathways after permanent focal ischemia in mice.

After an ischemic episode induced by the electrocoagulation of the left middle cerebral artery (MCA) in mouse, neurons within the damaged territory die either by an apoptotic or by a necrotic process. Most of the cortical neurons within the ischemic area display both morphological and biochemical signs of programmed cell death: nuclear condensation, DNA degradation, formation of apoptotic bodies, and glutathione depletion. In fact, apoptosis essentially contributes to the expansion of the ischemic lesion and the maximum of damaged territory is reached 24 h postocclusion. Several potentially neuroprotective pathways have been evidenced in different experimental models of ischemia including the activation of antioxidant enzyme activities and/or the recruitment of neurotrophic as well as antiapoptotic factors. In our model of permanent focal ischemia induced by MCA occlusion, we measured the temporal synthesis of nerve growth factor (NGF) and examined the status of antioxidant enzymes as well as Bcl-2 antiapoptotic product. We detected in both cortices a transient increase of NGF which peaks at 6 h. Moreover, we reported that glutathione peroxidase is recruited with a time course which parallels NGF synthesis. Finally, we observed the induction of Bcl-2 in safe neurons; this may represent a self-protective response against ischemia-induced apoptosis. We provide evidence that in a model of permanent focal ischemia, several neuroprotective pathways could be coactivated.

The expression pattern of somatostatin and calretinin by postnatal hippocampal interneurons is regulated by activity-dependent and -independent determinants.

Hippocampal interneurons form distinct populations identified on the basis of their projection pattern and neurochemical characteristics, which includes the expression of specific neuropeptides and/or calcium-binding proteins. The neurochemical maturation of hippocampal interneurons is largely a postnatal event, and factors which govern this maturation are presently unknown. Using slice cultures, we have investigated the role of neuronal activity in regulating the expression of somatostatin and calretinin during the postnatal maturation of hippocampal interneurons. Blocking inhibitory activity with bicuculline, or excitatory activity with 6,7-dinitroquinoxaline-2,3-dione, for 14 days in slice cultures from seven-day-old rat increased and decreased, respectively, the number of somatostatin-immunoreactive neurons. Withdrawal of the blocking agents resulted in a reversal of the effects on somatostatin immunoreactivity. In addition, bicuculline slightly increased the number of calretinin-positive neurons, while 6,7-dinitroquinoxaline-2,3-dione exerted no effect. However, bicuculline and 6,7-dinitroquinoxaline-2,3-dione markedly increased and decreased, respectively, the number of calretinin-labelled axons. Despite activity-linked modifications of immunoreactivity levels, no change in the organotypic location of somatostatin-labelled neurons was observed, whatever the treatment. Double labelling studies demonstrated that somatostatin and calretinin were expressed by different neurons, even when the number of labelled cells was highly increased. These results show that the levels of expression of somatostatin and calretinin in maturing hippocampal interneurons are tuned to the endogenous balance of excitatory and inhibitory activity. In contrast, the neurochemical specificity of each subtype of interneurons does not depend upon variations in neuronal activity.

Correlated axonal sprouting and dendritic spine formation during kainate-induced neuronal morphogenesis in the dentate gyrus of adult mice.

Several examples of structural plasticity in the adult brain have been provided in the hippocampus, among which the most striking concerns axonal remodeling of the dentate gyrus granule cells. We have recently demonstrated that a single injection of kainic acid into the dorsal hippocampus of adult mice triggers a conspicuous morphogenetic response of granule cells. Cellular labeling with biocytin 1, 2, and 4 weeks after injection of kainate revealed a progressive increase in dendritic thickness and length (up to 2.5-times), combined with an increase in the number of dendritic spines. This correlation resulted in the conservation of total spine density. No modifications of the dendritic arborization pattern were noted. In addition to dendritic changes, the number of axonal profiles observed within the hypertrophied granular layer and the inner part of the molecular layer appeared dramatically increased. Timm staining and anterograde labeling of two of the main extra-hippocampal afferent systems (i.e., septal, entorhinal) evidenced sprouting of mossy fibers and of septal afferents. Entorhinal fibers were not obviously modified. As revealed by calretinin-immunohistochemistry, commissural afferents also responded by an extensive sprouting. In addition, increases of dendritic spine number and dendritic length were noticeably greater in portions of dendrites that receive mossy fiber collaterals and septal and hypothalamic afferents, than in the external portion which receives entorhinal afferents. Although qualitative, this correlation suggests a relationship between kainate-induced structural plasticity of mature granule cells and the specific capacities of afferent systems to elaborate axon collaterals.

Distribution and role of aspartate in the nervous system of the chaetognath Sagitta.

Cholinergic control of locomotory muscles in chaetognaths is monitored by diffuse transmitter release through layers of collagen fibers that form the connective stratum of the hydroskeleton. Despite the lack of morphologically defined synaptic junctions, the control of locomotor activity in chaetognaths is highly specific and allows complex behavioral patterns. This complexity suggests the existence of neuromediators acting to modulate the effects of the main motor neurotransmitter, acetylcholine, on muscular contraction. Immunocytochemical investigations performed in Sagitta friderici by using antibodies directed against L-aspartate revealed the presence of the amino acid within abundant fiber networks regularly distributed in the head, trunk, and tail and within discrete groups of cell bodies. In addition to known components of the sensory and motor nervous systems, L-aspartate immunoreactivity revealed previously undescribed intraepidermal networks of axonal profiles. With the exception of two giant anterior fibers radiating from the ventral ganglion, L-aspartate-immunoreactive processes were usually thin and varicose, occasionally making an anastomosis. As indicated by electron microscopy, L-aspartate-immunoreactive varicosities apposed to the connective stratum were filled with synaptic-like vesicles but displayed no synaptic differentiation. Physiologic investigations suggested a potent inhibitory effect of L-aspartate on acetylcholine-induced muscle contraction. The wide distribution pattern of immunoreactive profiles suggests an important role of L-aspartate in motor and sensory functions in chaetognaths. Although classified among excitatory amino acids in vertebrates, aspartate may function as an inhibitory modulator of acetylcholine-induced muscle contraction in these enterocoelous gastroneuralians.

Characterization of beta-adrenergic receptors of freshly isolated astrocytes and neurons from rat brain.

The binding and characteristics of rat brain beta-adrenergic receptors (beta-AR) isolated from astrocytes and neurons were investigated. Equilibrium binding experiments demonstrated that beta-AR were more concentrated on astrocytes than on neurons isolated from forebrain, cerebral cortex and cerebellum. Inhibition experiments revealed that beta 1-AR and beta 2-AR were present in the two cell types. Isoproterenol revealed two interchangeable states of high and low affinity binding to both beta 1- and beta 2-AR in neurons. The high affinity binding sites were sensitive to guanylylimidodiphosphate (GppNHp). Similar results were found with other beta-AR agonists but not with salbutamol and salmeterol which recognized both affinity states of the neuronal beta 2-AR but only the low affinity state of beta 1-AR. In astrocytes only the low affinity state of beta-AR was observed.

Short increase of BDNF messenger RNA triggers kainic acid-induced neuronal hypertrophy in adult mice.

Neurotrophin gene expression in adult brain varies according to physiological activity and following brain injury, suggesting a role in neuronal maintenance and plasticity. However, the exact roles and mechanisms of action of neurotrophins in the adult brain are still poorly understood. We have recently demonstrated that neurons of the adult mouse dentate gyrus can develop a conspicuous morphogenetic response to intrahippocampal injection of kainic acid. This response is correlated with long-lasting overexpression of the brain-derived neurotrophic factor gene, suggesting a causal relationship between molecular and structural changes. To test this hypothesis, brain-derived neurotrophic factor messenger RNA were sequestered in vivo by administration of antisense oligodeoxynucleotides. When administered before 20 h post-kainate, antisense oligodeoxynucleotides totally prevented the kainate-induced neuronal hypertrophy, while sense or missense sequences had no effect. On the other hand, the hypertrophic response was observed when antisense administration was begun 24 h post-kainate, indicating an involvement of brain-derived neurotrophic factor messenger RNA in the initiation of structural changes, but not in their evolution. The hypertrophy was blocked by inhibition of tyrosine kinase activities by K252a, suggesting an involvement of Trk high affinity receptors. Administration of human recombinant brain-derived neurotrophic factor without previous treatment by kainate failed to induce any morphogenetic response. These results show that a short activation of the brain-derived neurotrophic factor gene can, in association with neuronal activation by kainate, trigger dramatic and long-lasting morphological changes in adult neurons. A physiological role of brain-derived neurotrophic factor in adult brain could therefore be to link, by autocrine/paracrine action, activation of glutamate receptors and neuronal morphological adaptive responses.

Morphogenetic effect of kainate on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor.

Intraperitoneal or intrahippocampal injections of kainate induce both hippocampal cell death and axonal remodeling of the dentate gyrus granular neurons. We report here that injection of kainate into the dorsal hippocampus of adult mice may also trigger a conspicuous and long-lasting global trophic response of granule cells. Morphological changes include somatic and dendritic growth and increased nuclear volume with ultrastructural features characteristic of neuronal development. The trophic response is correlated with a specific overexpression of brain-derived neurotrophic factor that is maintained for at least six months. This shows that plasticity in adult neurons can, in addition to axonal remodeling, extend to generalized cell growth. Our results further suggest that brain-derived neurotrophic factor could be involved in the activation and/or maintenance of this phenomenon.