Data from epidemiological studies suggest that the decline in estrogen following menopause could increase the risk of neurodegenerative diseases. Furthermore, experimental studies on different animal models have shown that estrogen is neuroprotective. The mechanisms involved in the neuroprotective effects of estrogen are still unclear. Anti-oxidant effects, activation of different membrane-associated intracellular signaling pathways, and activation of classical nuclear estrogen receptors (ERs) could contribute to neuroprotection. Interactions with neurotrophins and other growth factors may also be important for the neuroprotective effects of estradiol. In this review we focus on the interaction between insulin-like growth factor-I (IGF-I) and estrogen signaling in the brain and on the implications of this interaction for neuroprotection. During the development of the nervous system, IGF-I promotes the differentiation and survival of specific neuronal populations. In the adult brain, IGF-I is a neuromodulator, regulates synaptic plasticity, is involved in the response of neural tissue to injury and protects neurons against different neurodegenerative stimuli. As an endocrine signal, IGF-I represents a link between the growth and reproductive axes and the interaction between estradiol and IGF-I is of particular physiological relevance for the regulation of growth, sexual maturation and adult neuroendocrine function. There are several potential points of convergence between estradiol and IGF-I receptor (IGF-IR) signaling in the brain. Estrogen activates the mitogen-activated protein kinase (MAPK) pathway and has a synergistic effect with IGF-I on the activation of Akt, a kinase downstream of phosphoinositol-3 kinase. In addition, IGF-IR is necessary for the estradiol induced expression of the anti-apoptotic molecule Bcl-2 in hypothalamic neurons. The interaction of ERs and IGF-IR in the brain may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR, or on direct interactions of the signaling pathways of alpha and beta ERs and IGF-IR in the same cell, since most neurons expressing IGF-IR also express at least one of the ER subtypes. In addition, studies on adult ovariectomized rats given intracerebroventricular (i.c.v.) infusions with antagonists for ERs or IGF-IR or with IGF-I have shown that there is a cross-regulation of the expression of ERs and IGF-IR in the brain. The interaction of estradiol and IGF-I and their receptors may be involved in different neural events. In the developing brain, ERs and IGF-IR are interdependent in the promotion of neuronal differentiation. In the adult, ERs and IGF-IR interact in the induction of synaptic plasticity. Furthermore, both in vitro and in vivo studies have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of neural tissue to injury, suggesting that a parallel activation or co-activation of ERs and IGF-IR mediates neuroprotection.

The present studies compared the regulation of the neurotrophin ligands and receptors by estrogen in young adult and reproductively senescent rats. Both groups of animals were ovariectomized and replaced with 17beta-estradiol or placebo pellets for 4 weeks. Protein expression of specific neurotrophins and their receptors were measured in the olfactory bulb and its basal forebrain afferent, the horizontal limb of the diagonal band of Broca (hlDBB). Young-adult rats responded to estrogen with an increase in the expression of brain-derived neurotrophic factor (BDNF) in the olfactory bulb and hlDBB, as well as bulbar trkA and trkB receptors. Older rats did not respond to estrogen in this manner. Additionally, estrogen treatment decreased the expression of the universal neurotrophin receptor p75 in young adult animals, but increased expression of this receptor in reproductively senescent rats. The latter group, however, had significantly greater estrogen receptor alpha (ERalpha) expression in the olfactory bulb as compared to their younger counterparts, but very low expression of the steroid receptor coactivator, SRC-1. Changes in the proportion or ratio of steroid receptor/coactivator systems in the aging forebrain may contribute to the refractory response to estrogen in the reproductively senescent animals.

The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission and efficacy by increasing NMDA receptor activity. Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze. Spatial learning induced phosphorylation of TrkB, Fyn, and NR2B, but not NR2A, in the hippocampus. Fyn was coimmunoprecipitated with TrkB and NR2B, and this association was increased in well-trained rats compared with control animals. Continuous intracerebroventricular infusion of PP2, a tyrosine kinase inhibitor, in rats delayed memory acquisition in the radial arm maze, but PP2-treated animals reached the same level of learning as the controls. The phosphorylation of Fyn and NR2B, but not TrkB, was diminished by PP2 treatment. Our findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory in the hippocampus.

Low-threshold mechanoreceptor neurons (LTMs) of the dorsal root ganglia (DRG) are essential for touch sensation. They form highly specialized terminations in the skin and display stereotyped projections in the spinal cord. Functionally defined LTMs depend on neurotrophin signaling for their postnatal survival and functioning, but how these neurons arise during development is unknown. Here, we show that specific types of LTMs can be identified shortly after DRG genesis by unique expression of the MafA transcription factor, the Ret receptor and coreceptor GFRalpha2, and find that their specification is Ngn2 dependent. In mice lacking Ret, these LTMs display early differentiation defects, as revealed by reduced MafA expression, and at later stages their central and peripheral projections are compromised. Moreover, in MafA mutants, a discrete subset of LTMs display altered expression of neurotrophic factor receptors. Our results provide evidence that genetic interactions involving Ret and MafA progressively promote the differentiation and diversification of LTMs.

Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation.

The gene family of neurotrophins includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Recently, neurotrophin-5 (NT-5), a possible mammalian homologue to NT-4 described in the frog Xenopus, has been cloned in man and rat. The neurotrophins stimulate survival and differentiation of a range of target neurons by binding to cell surface receptors. The structure of NGF has recently been clarified from crystallographic data. The similarities between the different neurotrophins are substantial with the variable regions, giving specificity to each of the family members, being localized to some exposed loop regions. Low-affinity binding (Kd of 10(-9) M) of all tested neurotrophins is mediated via a 75 K glycoprotein (LNGFR) that has been cloned and characterized. A 140 K tyrosine protein kinase encoded by the proto-oncogene trk has been found to bind NGF with high affinity (Kd of 10(-11) M) and to evoke the cellular neurotrophic responses. In addition, a protein encoded by the trk-related gene trkB has been shown to bind BDNF. Recently, a third member of the trk family, trkC, has been cloned and demonstrated to function as a high-affinity receptor for NT-3. The expression of trk and LNGFR mRNA are co-localized in the rat brain to the medial septal nucleus and the nucleus of Broca's diagonal band containing the NGF-responsive magnocellular cholinergic neurons projecting to hippocampus and cerebral cortex. In sharp contrast, the pattern of expression of trkB is widely spread in many areas of the cortex as well as lateral septum. The trkB protein might serve general functions in large areas of the cortex. Site-directed mutagenesis and expression of recombinant chimaeric neurotrophin proteins have made it possible to localize a likely region for the interaction between NGF and the LNGFR. This region could be altered, resulting in the total loss of LNGFR binding by the mutant NGF protein without affecting the binding to the trk receptor which was sufficient for the full biological activity. Cladistic analysis of likely phylogenies within the neurotrophins shows BDNF and NT-4 to be most closely related whereas NGF may be the sister group to NT-3, BDNF, and NT-4. Neurotrophins offer obvious clinical possibilities for treatment of neurodegenerative diseases.

Axonal retrograde transport is essential for neuronal growth and survival. However, the nature and dynamics of the membrane compartments involved in this process are poorly characterized. To shed light on this pathway, we established an experimental system for the visualization and the quantitative study of retrograde transport in living motor neurons based on a fluorescent fragment of tetanus toxin (TeNT HC). Morphological and kinetic analysis of TeNT HC retrograde carriers reveals two major groups of organelles: round vesicles and fast tubular structures. TeNT HC carriers lack markers of the classical endocytic pathway and are not acidified during axonal transport. Importantly, TeNT HC and NGF share the same retrograde transport organelles, which are characterized by the presence of the neurotrophin receptor p75NTR. Our results provide the first direct visualization of retrograde transport in living motor neurons, and reveal a novel retrograde route that could be used both by physiological ligands (i.e., neurotrophins) and TeNT to enter the central nervous system.

Neurotrophins cooperate with neural activity to modulate CNS neuronal survival and dendritic differentiation. In a previous study, we demonstrated that a critical balance of neurotrophin and neural activity is required for Purkinje cell survival in cocultures of purified granule and Purkinje cells (Morrison and Mason, 1998). Here we investigate whether TrkB signaling regulates dendrite and spine development of Purkinje cells. BDNF treatment of purified Purkinje cells cultured alone did not elicit formation of mature dendrites or spines. In cocultures of granule and Purkinje cells, however, continuous treatment with BDNF over a 2 week postnatal culture period increased the density of Purkinje cell dendritic spines relative to controls without causing a shift in the proportions of headed and filopodia-like spines. The increase in spine number was blocked by adding TrkB-IgG to the medium together with BDNF. Although BDNF alone did not consistently modify the morphology of dendritic spines, treatment with TrkB-IgG alone yielded spines with longer necks than those in control cultures. None of these treatments altered Purkinje cell dendritic complexity. These analyses reveal a role for TrkB signaling in modulating spine development, consistent with recently reported effects of neurotrophins on synaptic function. Moreover, spine development can be uncoupled from dendrite outgrowth in this reductionist system of purified presynaptic and postsynaptic neurons.

Prosaposin was identified as a neurotrophic factor stimulating neurite outgrowth in murine neuroblastoma (NS20Y) cells and choline acetyltransferase (ChAT) activity in human neuroblastoma (SK-N-MC) cells. The four naturally occurring saposins, which are derived by proteolytic processing of prosaposin, were tested for activity. Saposin C was found to be active, whereas saposins A, B, and D were inactive as neurotrophic factors. Dose-response curves demonstrated that nanomolar concentrations of prosaposin and saposin C stimulated neurite outgrowth and increased ChAT activity. Prosaposin and saposin C exerted activity by a mechanism independent of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Binding assays utilizing saposin C as a ligand gave two saturable binding constants, a high-affinity (Kd = 19 pM) and a low-affinity (Kd = 1 nM) constant, with 2000 and 15,000 sites per NS20Y cell, respectively. Phosphorylation stimulation experiments demonstrated that brief treatment with prosaposin or saposin C enhanced phosphorylation of a variety of proteins, some of which contained phosphorylated tyrosine(s). Since both cell lines were also stimulated by ciliary neurotrophic factor (CNTF) as well as prosaposin, inhibition was tested by utilizing an anti-gp130 monoclonal antibody, which specifically inhibited CNTF stimulation; this antibody did not inhibit prosaposin or saposin C stimulation. These results indicate that prosaposin and saposin C are neurotrophic factors which initiate signal transduction by binding to a high-affinity receptor that induces protein phosphorylation.

The bipolar spiral ganglion neurons apparently delaminate from the growing cochlear duct and migrate to Rosenthal's canal. They project radial fibers to innervate the organ of Corti (type I neurons to inner hair cells, type II neurons to outer hair cells) and also project tonotopically to the cochlear nuclei. The early differentiation of these neurons requires transcription factors to regulate migration, pathfinding and survival. Neurog1 null mice lack formation of neurons. Neurod1 null mice show massive neuronal death combined with aberrant central and peripheral projections. Prox1 protein is necessary for proper type II neuron process navigation, which is also affected by the neurotrophins Bdnf and Ntf3. Neurotrophin null mutants show specific patterns of neuronal loss along the cochlea but remaining neurons compensate by expanding their target area. All neurotrophin mutants have reduced radial fiber growth proportional to the degree of loss of neurotrophin alleles. This suggests a simple dose response effect of neurotrophin concentration. Keeping overall concentration constant, but misexpressing one neurotrophin under regulatory control of another one results in exuberant fiber growth not only of vestibular fibers to the cochlea but also of spiral ganglion neurons to outer hair cells suggesting different effectiveness of neurotrophins for spiral ganglion neurite growth. Finally, we report here for the first time that losing all neurons in double null mutants affects extension of the cochlear duct and leads to formation of extra rows of outer hair cells in the apex, possibly by disrupting the interaction of the spiral ganglion with the elongating cochlea.

To test the hypothesis that neurotrophins might undergo significant changes in acute coronary syndrome (ACS), NGF and BDNF levels in sera of patients suffering of ACS and in control subjects were measured by enzyme-linked immunosorbent assay (ELISA). Plasma concentrations of glucose, total cholesterol, triglycerides, LDL, HDL, creatin kinase (CK), MB isoenzyme CK (CK-MB) were also measured with routine laboratory methods. We found reduced plasma levels of both NGF and BDNF in patients with ACS. These observations supports the hypothesis that one or both of these neurotrophins may be implicated in the pathogenesis of human coronary atherosclerosis.

Insulin-like growth factor-I (IGF-I), a 70-amino acid-protein structurally similar to insulin, promotes cell proliferation and differentiation in multiple tissues. Most of its effects are mediated by the Type I IGF receptor (IGF-IR), a heterotetramer that has tyrosine kinase activity and phosphorylates insulin receptor substrates (IRS-1 and 2) which leads to the activation of two downstream signaling cascades: the MAP kinase and the phosphatidylinositol 3-kinase (P3K) cascades. The growth-promoting effects of IGF-I are prominent in the nervous system, qualifying this molecule as a neurotrophin. Although the primary regulator of IGF-I expression is growth hormone (GH), the developmental expression of IGF-I in various tissues precedes that of GH, supporting an independent role of IGF-I in embryonic and fetal life [1]. This review will examine the effect of IGF-I on central nervous system (CNS) development. The specialized structure of the CNS is the product of a complex series of biological events which result from the interaction between the cells' genetic program and environmental influences. CNS development begins in the embryo with dorsal ectodermal cell proliferation to form the neural plate, and, with its closure, the neural tube, followed by the rapid division of pluripotential cells, their migration to the periphery of the neural tube, and differentiation into neural or glial cells. During the latter stages, cells form special structures such as nuclei, ganglia, cerebral cortical layers, and they also develop a network with their cytoplasmic extensions, neurites. Many more cells and connections are generated in fetal life than are found in the mature organism. This excessive production of some cell groups and neurites may compensate for tissue loss due to various injuries, and their selective elimination also constitutes an efficient way to organize the architecture of the CNS. This elimination is believed to be accomplished by apoptosis. The cells' intrinsic program for development includes the expression of various genes at different times. Environmental influences, such as extracellular matrix (ECM) molecules that attract or repel cells, afferent inputs, and target-derived diffusible molecules modify and modulate cellular behavior. IGF-I is among the molecules which affect several steps involved in development.

Erythropoietin, the principal regulator of erythroids progenitor cells, also promotes neuronal survival. Using primary cultures of rat hippocampal neurons, we investigated whether erythropoietin could mediate neuroprotection favouring the transcription of brain-derived neurotrophic factor (BDNF). Erythropoietin 2.7 nm reduced by approximately 50% the neuronal death triggered by the prototypic neurotoxicant trimethyltin (TMT) and time-dependently induced BDNF mRNA. This effect resulted in an increased production of biologically active BDNF, which led to a sustained activation of the specific BDNF receptor tyrosine kinase B (TrkB). Reduction of TMT-induced neuronal death by erythropoietin was specifically prevented by a neutralizing anti-BDNF antibody (15 microg/mL), indicating the involvement of this neurotrophin in erythropoietin neuroprotective effect. Intracerebroventricular administration of erythropoietin in mice significantly increases BDNF mRNA expression in brain, supporting the idea of the involvement of this neurotrophin in erythropoietin action within the CNS. BDNF expression in neuronal cells is induced by activation of voltage Ca(2+)-channels and recruitment of Ca(2+)-sensitive transcription factors. Consistently, 2.7 nm erythropoietin increased intracellular Ca(2+) in 5 min and cAMP response element binding protein (CREB) phosphorylation at Ser 133 in 30 min. Both effects were abolished by 1 microm nitrendipine, a selective blocker of L-type voltage Ca(2+)-channels. These data demonstrate that erythropoietin activates the CREB transcription pathway and increases BDNF expression and production, which contributes to erythropoietin mediated neuroprotection.

The neurotrophin brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal survival, synaptic plasticity, and memory. Several recent studies have demonstrated altered BDNF serum levels in Alzheimer's disease (AD) patients. However, the association of BDNF serum levels with the rate of cognitive decline in AD patients is still unclear. We demonstrate that BDNF serum levels are significantly decreased in AD patients with fast cognitive decline [decrease of Mini-Mental State Examination (MMSE) score >4/yr; n=12] compared to AD patients with slow cognitive decline (decrease of MMSE score ≤4/yr, n=28) and show a significant correlation with the rate of cognitive decline during 1 yr follow-up. These results suggest that higher BDNF serum levels are associated with a slower rate of cognitive decline in AD patients. Further longitudinal studies are necessary to elucidate the kinetics and the potential role of serum BDNF as a surrogate marker of disease progression in AD patients.

It is widely recognized that methamphetamine enhances the release of dopamine at dopaminergic neuron terminals of the mesolimbic system, which induces dopamine-related behaviors. Brain-derived neurotrophic factor (BDNF), a neurotrophin, binds to and activates its specific receptor tyrosine kinase, TrkB. BDNF has been shown to influence the release of dopamine in the mesolimbic dopamine system. The present study was designed to investigate roles of BDNF and TrkB in the expression of methamphetamine-induced dopamine release in the nucleus accumbens and dopamine-related behaviors induced by methamphetamine in rats. Methamphetamine (1 mg/kg, s.c.) produced a substantial increase in the extracellular levels of dopamine and induced a progressive augmentation of dopamine-related behaviors such as rearing and sniffing. In contrast, both the stimulation of dopamine release and induction of dopamine-related behaviors by methamphetamine were significantly suppressed by pretreatment with intra-nucleus accumbens injection of either BDNF (2.0 microl/rat, 1:1000, 1:300 and 1:100) or TrkB (2.0 microl/rat, 1:1000 and 1:100) antibody. Furthermore, the basal level of dopamine in the nucleus accumbens was not affected by treatment with both BDNF and TrkB antibodies. These findings provide further evidence that BDNF/TrkB pathway is implicated in the methamphetamine-induced release of dopamine and the induction of dopamine-related behaviors.

A member of the neurotrophin family, brain-derived neurotrophic factor (BDNF) regulates neuronal survival and differentiation during development. Within the adult brain, BDNF is also important in neuronal adaptive processes, such as the activity-dependent plasticity that underlies learning and memory. These long-term changes in synaptic strength are mediated through alterations in gene expression. However, many of the mechanisms by which BDNF is linked to transcriptional and translational regulation remain unknown. Recently, the transcription factor NFATc4 (nuclear factor of activated T-cells isoform 4) was discovered in neurons, where it is believed to play an important role in long-term changes in neuronal function. Interestingly, NFATc4 is particularly sensitive to the second messenger systems activated by BDNF. Thus, we hypothesized that NFAT-dependent transcription may be an important mediator of BDNF-induced plasticity. In cultured rat CA3-CA1 hippocampal neurons, BDNF activated NFAT-dependent transcription via TrkB receptors. Inhibition of calcineurin blocked BDNF-induced nuclear translocation of NFATc4, thus preventing transcription. Further, phospholipase C was a critical signaling intermediate between BDNF activation of TrkB and the initiation of NFAT-dependent transcription. Both inositol 1,4,5-triphosphate (IP3)-mediated release of calcium from intracellular stores and activation of protein kinase C were required for BDNF-induced NFAT-dependent transcription. Finally, increased expression of IP3 receptor 1 and BDNF after neuronal exposure to BDNF was linked to NFAT-dependent transcription. These results suggest that NFATc4 plays a crucial role in neurotrophin-mediated synaptic plasticity.

The expression of neurotrophins (NTs) and related high- and low-affinity receptors was studied in surgical samples of histologically diagnosed human tumors of the lower respiratory tract. The experiment was conducted with 30 non-small cell lung cancer specimens and in eight small cell lung cancer specimens by Western blot analysis and immunohistochemistry to assess expression and distribution of NT and NT receptor proteins in tissues examined. Immunoblots of homogenates from human tumors displayed binding of anti-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and NT-3 antibodies as well as of anti-tyrosine-specific protein kinase (Trk) A, TrkB, and TrkC receptor antibodies, with similar migration characteristics than those displayed by human beta-NGF and proteins from rat brain. A specific immunoreactivity for NTs and NT receptors was demonstrated in vessel walls, stromal fibroblasts, immune cells, and sometimes within neoplastic cell bodies. Approximately 33% of bronchioloalveolar carcinomas exhibited a strong membrane NGF and TrkA immunoreactivity, whereas 46% adenocarcinomas expressed an intense TrkA immunoreactivity but a weak immunostaining for NGF within tumor cells. Moreover, squamous cell carcinomas developed an intense TrkA immunoreactivity only within stroma surrounding neoplastic cells. A faint BDNF and TrkB immunoreactivity was documented in adenocarcinomas, squamous cell carcinomas, and small cell lung cancers. NT-3 and its corresponding TrkC receptor were found in a small number of squamous cell carcinomas within large-size tumor cells. No expression of low-affinity p75 receptor protein was found in tumor cells. The detection of NTs and NT receptor proteins in tumors of the lower respiratory tract suggests that NTs may be involved in controlling growth and differentiation of human lung cancer and/or influencing tumor behavior.

Brain-derived neurotrophic factor (BDNF) plays an important role in development, synapse remodelling and responses to stress and injury. Its abnormal expression has been implicated in schizophrenia, a neuropsychiatric disorder in which abnormal neural development of the hippocampus and prefrontal cortex has been postulated. To clarify the effects of antipsychotic drugs used in the therapy of schizophrenia on BDNF mRNA, we studied its expression in rats treated with clozapine and haloperidol and in rats with neonatal lesions of the ventral hippocampus, used as an animal model of schizophrenia. Both antipsychotic drugs reduced BDNF expression in the hippocampus of control rats, but did not significantly lower its expression in the prefrontal cortex. The neonatal hippocampal lesion itself suppressed BDNF mRNA expression in the dentate gyrus and tended to reduce its expression in the prefrontal cortex. These results indicate that, unlike antidepressants, antipsychotics down-regulate BDNF mRNA, and suggest that their therapeutic properties are not mediated by stimulation of this neurotrophin. To the extent that the lesioned rat models some pathophysiological aspects of schizophrenia, our data suggest that a neurodevelopmental insult might suppress expression of the neurotrophin in certain brain regions.

This commentary reviews selected biomedical and clinical research examining the relationship between physical exercise and cognitive function especially in youth with disability. Youth with physical disability may not benefit from the effects of exercise on cardiovascular fitness and brain health since they are less active than their non-disabled peers. In animal models, physical activity enhances memory and learning, promotes neurogenesis and protects the nervous system from injury and neurodegenerative disease. Neurotrophins, endogenous proteins that support brain plasticity likely mediate the beneficial effects of exercise on the brain. In clinical studies, exercise increases brain volume in areas implicated in executive processing, improves cognition in children with cerebral palsy and enhances phonemic skill in school children with reading difficulty. Studies examining the intensity of exercise required to optimize neurotrophins suggest that moderation is important. Sustained increases in neurotrophin levels occur with prolonged low intensity exercise, while higher intensity exercise, in a rat model of brain injury, elevates the stress hormone, corticosterone. Clearly, moderate physical activity is important for youth whose brains are highly plastic and perhaps even more critical for young people with physical disability.

Two G protein-coupled receptors for marijuana's psychoactive component, Delta9-tetrahydrocannabinol, have been cloned to date, the cannabinoid CB1 and CB2 receptors. These two proteins, the endogenous lipids that activate them, also known as endocannabinoids, and the proteins for the biosynthesis and inactivation of these ligands constitute the endocannabinoid system. Evidence has accumulated over the last few years suggesting that endocannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. In fact, exogenous and endogenous cannabinoids were shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by cannabinoid CB1-mediated inhibition of glutamatergic transmission, reduction of calcium influx, anti-oxidant activity, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, induction of phosphorylation of extracellular regulated kinases and the expression of transcription factors and neurotrophins, lowering of cerebrovasoconstriction and induction of hypothermia. The release of endocannabinoids during neuronal injury may constitute a protective response. If this neuroprotective function of cannabinoid receptor activation can be transferred to the clinic, it might represent an interesting target to develop neuroprotective agents.

The "glucocorticoid cascade hypothesis" of hippocampal aging has stimulated a great deal of research into the neuroendocrine aspects of aging and the role of glucocorticoids, in particular. Besides strengthening the methods for investigating the aging brain, this research has revealed that the interactions between glucocorticoids and hippocampal neurons are far more complicated than originally envisioned and involve the participation of neurotransmitter systems, particularly the excitatory amino acids, as well as calcium ions and neurotrophins. New information has provided insights into the role of early experience in determining individual differences in brain and body aging by setting the reactivity of the hypothalamopituitary-adrenal axis and the autonomic nervous system. As a result of this research and advances in neuroscience and the study of aging, we now have a far more sophisticated view of the interactions among genes, early development, and environmental influences, as well as a greater appreciation of events at the cellular and molecular levels which protect neurons, and a greater appreciation of pathways of neuronal damage and destruction. While documenting the ultimate vulnerability of the brain to stressful challenges and to the aging process, the net result of this research has highlighted the resilience of the brain and offered new hope for treatment strategies for promoting the health of the aging brain.

Seizure causes neuronal cell loss in both animal models and human epilepsy. To determine the contribution of apoptotic mechanisms to seizure-induced neuronal cell death, rat brains were examined for the occurrence of terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive nuclei after pilocarpine-induced seizure. Numerous TUNEL-positive cells were observed throughout the postseizure hippocampus, piriform cortex, and entorhinal cortex. Combined TUNEL/NeuN immunocytochemistry demonstrated that the vast majority of TUNEL-positive cells were neurons. To identify components of the signal transduction cascade promoting postseizure apoptosis, the expression of the p75 neurotrophin receptor (p75NTR) was examined. Seizure-induced increases in p75NTR protein and mRNA were detected in hippocampus, piriform cortex, and entorhinal cortex. Immunohistochemical double labeling revealed almost complete correspondence between TUNEL-positive and p75NTR-expressing cells, suggesting that seizure-induced neuronal loss within the CNS occurs through apoptotic signaling cascades involving p75NTR.

Synapse formation requires contact between dendrites and axons. Although this process is often viewed as axon mediated, dendritic filopodia may be actively involved in mediating synaptogenic contact. Although the signaling cues underlying dendritic filopodial motility are mostly unknown, brain-derived neurotrophic factor (BDNF) increases the density of dendritic filopodia and conditional deletion of tyrosine receptor kinase B (TrkB) reduces synapse number in vivo. Here, we report that TrkB associates with dendritic growth cones and filopodia, mediates filopodial motility, and does so via the phosphoinositide 3 kinase (PI3K) pathway. We used genetic and pharmacological manipulations of mouse hippocampal neurons to assess signaling downstream of TrkB. Conditional knock-out of two downstream negative regulators of TrkB signaling, Pten (phosphatase with tensin homolog) and Nf1 (neurofibromatosis type 1), enhanced filopodial motility. This effect was PI3K-dependent and correlated with synaptic density. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) was preferentially localized in filopodia and this distribution was enhanced by BDNF application. Thus, intracellular control of filopodial dynamics converged on PI3K activation and PIP3 accumulation, a cellular paradigm conserved for chemotaxis in other cell types. Our results suggest that filopodial movement is not random, but responsive to synaptic guidance molecules.

The influence of neurotrophins on GABAergic properties of developing striatal neurons was investigated both in vivo and in vitro. Brain-derived neurotrophic factor (BDNF) specifically elevated cellular GABA content in striatal culture without altering neuronal survival. Neurotrophin-5 produced a similar effect on GABA, but nerve growth factor and neurotrophin-3 had no effect. An increase in GABA content in the striatum was also observed following BDNF injections into the cerebroventricle of neonatal rats. The increase of GABA levels in culture mainly resulted from an increase in holoenzyme activity of the GABA synthetic enzyme glutamic acid decarboxylase (GAD) and elevation of GABA uptake activity. In BDNF-treated striatal cultures, the newly differentiated neurons extended elaborate neurites and exhibited strong GAD immunoreactivity. These alterations were presumably caused by the upregulation of mRNA encoding GAD67 and the neuronal GABA transporter GAT-1. BDNF treatment also promoted other phenotypic differentiation of striatal neurons: BDNF increased the frequency of parvalbumin-immunoreactive neurons and calbindin-immunoreactive neurons and neuropeptide content for neuropeptide Y and somatostatin. These observations suggest that neurotrophins may contribute to phenotypic differentiation of GABAergic neurons in the developing striatum.