Neurotrophins bind to two structurally unrelated receptors, the trk tyrosine kinases and the neurotrophin receptor p75(NTR). Ligand activation of these two types of receptor can lead to opposite actions, in particular the prevention or activation of programmed cell death. Many cells co-express trk receptors and p75(NTR), and we found that p75(NTR) was co-precipitated with trkA, trkB and trkC in cells transfected with both receptor types. Co-precipitation of p75(NTR) was not observed with the epidermal growth factor receptor. Experiments with deletion constructs of trkB (the most abundant trk receptor in the brain) and p75(NTR) revealed that both the extracellular and intracellular domains of trkB and p75(NTR) contribute to the interaction. Blocking autophosphorylation of trkB substantially reduced the interactions between p75(NTR) and trkB constructs containing the intracellular, but not the extracellular, domains. We also found that co-expression of p75(NTR) with trkB resulted in a clear increase in the specificity of trkB activation by brain-derived neurotrophic factor, compared with neurotrophin-3 and neurotrophin-4/5. These results indicate a close proximity of the two neurotrophin receptors within cell membranes, and suggest that the signalling pathways they initiate may interact soon after their activation.

Since the identification of the first MAGE gene in 1991, the MAGE family has expanded dramatically, and over 25 MAGE genes have now been identified in humans. The focus of studies on the MAGE proteins has been their potential for cancer immunotherapy, as a result of the finding that peptides derived from MAGE gene products are bound by major histocompatibility complexes and presented on the cell surface of cancer cells. However, the normal physiological role of MAGE proteins has remained a mystery. Recent studies are now beginning to provide insights into MAGE gene function. Necdin acts as a cell cycle regulatory protein and plays a key role in the pathogenesis of Prader-Willi syndrome, a neurogenetic disorder. MAGE-D1, identified as a binding partner for the p75 neurotrophin receptor, the apoptosis inhibitory protein XIAP, and Dlx/MSX homeodomain proteins, blocks cell cycle progression and enhances apoptosis. This review provides an overview of the human MAGE genes and proteins, summarizes recent findings on their cellular roles, and provides a baseline for future studies on this intriguing gene family.

Previous attempts to promote regeneration after spinal cord injury have succeeded in stimulating axonal growth into or around lesion sites but rarely beyond them. We tested whether a combinatorial approach of stimulating the neuronal cell body with cAMP and the injured axon with neurotrophins would propel axonal growth into and beyond sites of spinal cord injury. A preconditioning stimulus to sensory neuronal cell bodies was delivered by injecting cAMP into the L4 dorsal root ganglion, and a postinjury stimulus to the injured axon was administered by injecting neurotrophin-3 (NT-3) within and beyond a cervical spinal cord lesion site grafted with autologous bone marrow stromal cells. One to 3 months later, long-projecting dorsal-column sensory axons regenerated into and beyond the lesion. Regeneration beyond the lesion did not occur after treatment with cAMP or NT-3 alone. Thus, clear axonal regeneration beyond spinal cord injury sites can be achieved by combinatorial approaches that stimulate both the neuronal soma and the axon, representing a major advance in strategies to enhance spinal cord repair.

There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5). Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.

Despite high enthusiasm, early attempts to develop clinical treatments based on animal research with neurotrophins were not successful. Here we survey clinical trials with neurotrophins, compared with neurotrophic factors of other gene families, and delineate the most likely reasons for their failure. We then suggest improved methods for regulated local supply of NTs to specific populations of neurons and discuss future therapeutic procedures evolving from the more detailed knowledge of the signal transduction pathways activated by neurotrophins via their receptors.

The initial event in the neuronal differentiation of PC12 cells is the binding of the neurotrophin nerve growth factor (NGF) to the Trk receptor. This interaction stimulates the intrinsic tyrosine kinase activity of Trk, initiating a signalling cascade involving the phosphorylation of intracellular proteins on tyrosine, serine, and threonine residues. These signals are then in turn propagated to other messengers, ultimately leading to differentiation, neurotrophin-dependent survival, and the loss of proliferative capacity. To transmit NGF signals, NGF-activated Trk rapidly associates with the cytoplasmic proteins, SHC, PI-3 kinase, and PLC-gamma 1. These proteins are involved in stimulating the formation of various second messenger molecules and activating the Ras signal transduction pathway. Studies with Trk mutants indicate that the activation of the Ras pathway is necessary for complete differentiation of PC12-derived cells and for the maintenance of the differentiated phenotype. Trk also induces the tyrosine phosphorylation of SNT, a specific target of neurotrophic factor activity in neuronal cells. This review will discuss the potential roles of Trk and the proteins of the Trk signalling pathways in NGF function, and summarize our attempts to understand the mechanisms used by Trk to generate the many phenotypic responses of PC12 cells to NGF.

The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA binding activity and transactivation activity of AP-1 transcription factors, as well as the expression of genes regulated by AP-1, in cultured cells and brain regions involved in mood regulation. In the present study, we found that VPA activated extracellular signal-regulated kinase (ERK), a kinase known to regulate AP-1 function and utilized by neurotrophins to mediate their diverse effects, including neuronal differentiation, neuronal survival, long term neuroplasticity, and potentially learning and memory. VPA-induced activation of ERK was blocked by the mitogen-activated protein kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf mutants but not by dominant-negative stress-activated protein kinase/ERK kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and Bcl-2, promoted neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data demonstrate that VPA is an ERK pathway activator and produces neurotrophic effects.

It is well accepted that events that interfere with the normal program of neuronal differentiation and brain maturation may be relevant for the etiology of psychiatric disorders, setting the stage for synaptic disorganization that becomes functional later in life. In order to investigate molecular determinants for these events, we examined the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) and the glutamate NMDA receptor following 24 h maternal separation (MD) on postnatal day 9. We found that in adulthood the expression of BDNF as well as of NR-2A and NR-2B, two NMDA receptor forming subunits, were significantly reduced in the hippocampus of MD rats whereas, among other structures, a slight reduction of NR-2A and 2B was detected only in prefrontal cortex. These changes were not observed acutely, nor in pre-weaning animals. Furthermore we found that in MD rats the modulation of hippocampal BDNF in response to an acute stress was altered, indicating a persistent functional impairment in its regulation, which may subserve a specific role for coping with challenging situations. We propose that adverse events taking place during brain maturation can modulate the expression of molecular players of cellular plasticity within selected brain regions, thus contributing to permanent alterations in brain function, which might ultimately lead to an increased vulnerability for psychiatric diseases.

Schwann cells in developing and regenerating peripheral nerves express elevated levels of the neurotrophin receptor p75NTR. Neurotrophins are key mediators of peripheral nervous system myelination. Our results show that myelin formation is inhibited in the absence of functional p75NTR and enhanced by blocking TrkC activity. Moreover, the enhancement of myelin formation by endogenous brain-derived neurotrophic factor is mediated by the p75NTR receptor, whereas TrkC receptors are responsible for neurotrophin-3 inhibition. Thus p75NTR and TrkC receptors have opposite effects on myelination.

Alterations in the inhibitory circuitry of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia include reduced expression of the messenger RNA (mRNA) for somatostatin (SST), a neuropeptide present in a subpopulation of gamma-aminobutyric acid (GABA) neurons. However, neither the cellular substrate nor the causal mechanisms for decreased SST mRNA levels in schizophrenia are known. We used in situ hybridization to quantify the compartmental, laminar, and cellular levels of SST mRNA expression in the DLPFC of 23 pairs of schizophrenia or schizoaffective disorder and control subjects. We also explored potential causal mechanisms by utilizing similar methods to analyze SST mRNA expression in 2 animal models. The expression of SST mRNA was significantly decreased in layers 2-superficial 6 of subjects with schizophrenia, but not in layer 1, deep 6 or the white matter. At the cellular level, both the density of cortical SST mRNA-positive neurons and the expression of SST mRNA per neuron were reduced in the subjects with schizophrenia. These alterations were not due to potential confounds and appeared to be a downstream consequence of impaired neurotrophin signaling through the trkB receptor. These findings support the hypothesis that a marked reduction in SST mRNA expression in a subset of GABA neurons contributes to DLPFC dysfunction in schizophrenia.

The neurotrophin receptor TrkB is essential for normal function of the mammalian brain. It is expressed in three splice variants. Full-length receptors (TrkB(FL)) possess an intracellular tyrosine kinase domain and are considered as those TrkB receptors that mediate the crucial effects of brain-derived neurotrophic factor (BDNF) or neurotrophin 4/5 (NT-4/5). By contrast, truncated receptors (TrkB-T1 and TrkB-T2) lack tyrosine kinase activity and have not been reported to elicit rapid intracellular signalling. Here we show that astrocytes predominately express TrkB-T1 and respond to brief application of BDNF by releasing calcium from intracellular stores. The calcium transients are insensitive to the tyrosine kinase blocker K-252a and persist in mutant mice lacking TrkB(FL). By contrast, neurons produce rapid BDNF-evoked signals through TrkB(FL) and the Na(v)1.9 channel. Expression of antisense TrkB messenger RNA strongly reduces BDNF-evoked calcium signals in glia. Thus, our results show that, unexpectedly, TrkB-T1 has a direct signalling role in mediating inositol-1,4,5-trisphosphate-dependent calcium release; in addition, they identify a previously unknown mechanism of neurotrophin action in the brain.

Local infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) can prevent and reverse the ability of chronic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) in this brain region. The present study examined a possible role for extracellular signal regulated kinases (ERKs), the major effector for BDNF and related neurotrophins, in morphine and cocaine action in the VTA. Chronic, but not acute, administration of morphine or cocaine increased ERK catalytic activity specifically in the VTA. This increase in ERK activity reflected an increase in the state of phosphorylation of ERK, with no change in levels of total ERK immunoreactivity. Chronic infusions of BDNF into the VTA reduced total ERK immunoreactivity with no change in ERK activity, and also blocked the morphine-induced increase in ERK activity. These results suggest that chronic BDNF elicits a compensatory increase in the phosphorylation of the remaining ERK molecules and thereby prevents any additional increase in response to drug exposure. Such a role for ERK in morphine action was demnostrated directly by chronically infusing antisense oligonucleotides to ERK1 into the VTA. This treatment selectively reduced levels of ERK1 immunoreactivity in a sequence-specific manner without detectable toxicity. Intra-VTA infusion of ERK1 antisense oligonucleotides mimicked the effects of chronic BDNF infusions on ERK immunoreactivity, ERK activity, and TH immunoreactivity in the VTA under both control and morphine-treated conditions. The chronic morphine-induced increases in ERK activity and TH expression in the VTA also were blocked by local infusion of NMDA glutamate receptor antagonists, suggesting a role for glutamate in mediating these drug effects. Together, these findings support a scheme whereby chronic, systemic administration of morphine or cocaine leads to a sustained increase in ERK phosphorylation state and activity in the VTA, which, in turn, contributes to drug-induced increases in TH, and perhaps other drug-induced adaptations, elicited selectively in this brain region.

The chronic mild (or unpredictable/variable) stress (CMS) model was developed as an animal model of depression more than 20 years ago. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that was akin to the anhedonia observed in major depressive disorder. In the time since its inception, this model has also been used for a variety of studies examining neurobiological variables that are associated with depression, despite the fact that this model has never been critically examined to validate that the neurobiological changes induced by CMS are parallel to those documented in depressive disorder. The aim of the current review is to summarize the current state of knowledge regarding the effects of chronic mild stress on neurobiological variables, such as neurochemistry, neurochemical receptor expression and functionality, neurotrophin expression and cellular plasticity. These findings are then compared to those of clinical research examining common variables in populations with depressive disorders to determine if the changes observed following chronic mild stress are in fact consistent with those observed in major depression. We conclude that the chronic mild stress paradigm: (1) evokes an array of neurobiological changes that mirror those seen in depressive disorders and (2) may be a suitable tool to investigate novel systems that could be disturbed in depression, and thus aid in the development of novel targets for the treatment of depression.

The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases for neurotrophins of a nerve growth factor (NGF) family. The Trk signals spatiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the receptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and medulloblastoma. The intracellular Trk signaling pathway is also different depending on the Trk family receptors, cell types and the grade of transformation. Furthermore, developmentally programmed cell death of neuron, which is largely regulated by neurotrophin signaling, is at least in part controlled by tumor suppressors p53 and p73 as well as their antagonist DeltaNp73. Thus, the Trks and their downstream signaling function in both ontogenesis and oncogenesis. In this short review, the dynamic role of the Trk family receptors signaling in neural development, neurogenic tumors and other cancers will be discussed.

Rubrospinal neurons (RSNs) undergo a marked atrophy in the second week after cervical axotomy. This delayed atrophy is accompanied by a decline in the expression of regeneration-associated genes such as GAP-43 and Talpha1-tubulin, which are initially elevated after injury. These responses may reflect a deficiency in the trophic support of axotomized RSNs. To test this hypothesis, we first analyzed the expression of mRNAs encoding the trk family of neurotrophin receptors. In situ hybridization revealed expression of full-length trkB receptors in virtually all RSNs, which declined 7 d after axotomy. Full-length trkC mRNA was expressed at low levels. Using RT-PCR, we found that mRNAs encoding trkC isoforms with kinase domain inserts were present at levels comparable to that for the unmodified receptor. TrkA mRNA expression was not detected in RSNs, and the expression of p75 was restricted to a small subpopulation of axotomized cells. In agreement with the pattern of trk receptor expression, infusion of recombinant human BDNF or NT-4/5 into the vicinity of the axotomized RSNs, between days 7 and 14 after axotomy, fully prevented their atrophy. This effect was still evident 2 weeks after the termination of BDNF treatment. Moreover, BDNF or NT-4/5 treatment stimulated the expression of GAP-43 and Talpha1-tubulin mRNA and maintained the level of trkB expression. Vehicle, NGF, or NT-3 treatment had no significant effect on cell size or GAP-43 and Talpha1-tubulin expression. In a separate experiment, infusion of BDNF also was found to increase the number of axotomized RSNs that regenerated into a peripheral nerve graft. Thus, in BDNF-treated animals, the prevention of neuronal atrophy and the stimulation GAP-43 and Talpha1-tubulin expression is correlated with an increased regenerative capacity of axotomized RSNs.

Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) are the three members of the neurotrophin family known to exist in mammals. Recently, a fourth neurotrophin (designated neurotrophin-4 or NT-4), which shares all of the features found in the mammalian neurotrophins, has been identified in Xenopus and viper. We used sequences specific to the Xenopus/viper NT-4 to isolate a neurotrophin from both human and rat genomic DNA that appears to represent the mammalian counterpart of Xenopus/viper NT-4. Human NT-4 as well as a human NT-4 pseudogene colocalize to chromosome 19 band q13.3. Mammalian NT-4 has many unusual features compared to the previously identified neurotrophins and is less conserved evolutionarily than the other neurotrophins. However, mammalian NT-4 displays bioactivity and trk receptor specificity similar to that of Xenopus NT-4.

Epilepsy, a disorder of recurrent seizures, is a common and frequently devastating neurological condition. Available therapy is only symptomatic and often ineffective. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help identify molecular targets for drugs that could prevent epilepsy. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of epileptogenesis have been established. Here, we review current insights into the molecular signaling mechanisms underlying epileptogenesis, focusing on limbic epileptogenesis. Study of different models reveals that activation of various receptors on the surface of neurons can promote epileptogenesis; these receptors include ionotropic and metabotropic glutamate receptors as well as the TrkB neurotrophin receptor. These receptors are all found in the membrane of a discrete signaling domain within a particular type of cortical neuron--the dendritic spine of principal neurons. Activation of any of these receptors results in an increase Ca2+ concentration within the spine. Various Ca2+-regulated enzymes found in spines have been implicated in epileptogenesis; these include the nonreceptor protein tyrosine kinases Src and Fyn and a serine-threonine kinase [Ca2+-calmodulin-dependent protein kinase II (CaMKII)] and phosphatase (calcineurin). Cross-talk between astrocytes and neurons promotes increased dendritic Ca2+ and synchronous firing of neurons, a hallmark of epileptiform activity. The hypothesis is proposed that limbic epilepsy is a maladaptive consequence of homeostatic responses to increases of Ca2+ concentration within dendritic spines induced by abnormal neuronal activity.

The TrkB family of transmembrane proteins serve as receptors for brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-4/5, and possibly NT-3, three members of the neurotrophin family of neurotrophic factors. In order to understand the potential roles played by these receptors, we have examined the distribution of the TrkB receptor proteins in the adult rat brain by using immunohistochemistry. Several different antisera, directed against either synthetic peptides corresponding to different regions of TrkB or a recombinant fusion protein comprising part of the extracellular domain, were generated. Each of these antisera was directed to epitopes found on all known TrkB isoforms (both the tyrosine kinase-possessing isoform and the truncated kinase-lacking isoforms). In addition, a commercially available antibody to the intracellular domain of TrkB was also used. Widespread and distinct staining was observed on the surface of neuronal cell bodies, axons, and dendrites in many structures, including the cerebral cortex, hippocampus, dentate gyrus, striatum, septal nuclei, substantia nigra, cerebellar Purkinje cells, brainstem and spinal motor neurons, and brainstem sensory nuclei. Staining was also observed in the pia matter, on a subpopulation of ependymal cells lining the cerebral ventricle wall, and other nonneuronal cells. The expression pattern of TrkB receptor protein suggests that TrkB plays a broad role in the central nervous system. In addition, the detection of TrkB immunoreactivity on cell bodies and dendrites is consistent with recent models suggesting that neurotrophins may be derived from presynaptic and/or autocrine sources in addition to the classical postsynaptic target.

Recent studies suggest that the injured adult spinal cord responds to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) with enhanced neuron survival and axon regeneration. Potential neurotrophin sources and cellular localization in spinal cord are largely undefined. We examined glial BDNF localization in normal cord and its temporospatial distribution after injury in vivo. We used dual immunolabeling for BDNF and glial fibrillary acidic protein (GFAP) in astrocytes, adenomatous polyposis coli tumor suppressor protein (APC) for oligodendrocytes or type III CDH receptor (OX42) for microglia/macrophages. In normal cord, small subsets of astrocytes and microglia/macrophages and most oligodendrocytes exhibited BDNF-immunoreactivity. Following injury, the number of BDNF-immunopositive astrocytes and microglia/macrophages increased dramatically at the injury site over time. Most oligodendrocytes contained BDNF 1 day and 1 week following injury, but APC-positive cells were largely absent at the injury site 6 weeks postinjury. Glial BDNF-immunolabeling was also examined 10 and 20 mm from the wound. Ten millimeters from the lesion, astrocyte and microglia/macrophage BDNF-immunolabeling resembled that at the injury at all times examined. Twenty millimeters from injury, BDNF localization in all three glial subtypes resembled controls, regardless of time postlesion. Our findings suggest that in normal adult cord, astrocytes, oligodendrocytes, and microglia/macrophages play roles in local trophin availability and in trophin-mediated injury and healing responses directly within and surrounding the wound site.

The oncogenic epithelial-mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor β (TGF-β) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis.

The inability of CNS axons to regenerate after traumatic spinal cord injury is due, in part, to the inhibitory effects of myelin. The three major previously identified constituents of this activity (Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein) were isolated based on their potent inhibition of axon outgrowth in vitro. All three myelin components transduce their inhibitory signals through the same Nogo receptor/p75 neurotrophin receptor/LINGO-1 (NgR1/p75/LINGO-1) complex. In this study, we considered that molecules known to act as repellants in vertebrate embryonic axonal pathfinding may also inhibit regeneration. In mice, ephrin-B3 functions during development as a midline repellant for axons of the corticospinal tract. We therefore investigated whether this repellant was expressed in the adult spinal cord and retained inhibitory activity. We demonstrate that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and, by using primary CNS neurons, show that ephrin-B3 accounts for an inhibitory activity equivalent to that of the other three myelin-based inhibitors, acting through p75, combined. Our data describe a known vertebrate axon guidance molecule as a myelin-based inhibitor of neurite outgrowth.

BACKGROUND

In aging mice, activity maintains hippocampal plasticity and adult hippocampal neurogenesis at a level corresponding to a younger age. Here we studied whether physical exercise and environmental enrichment would also affect brain plasticity in a mouse model of Alzheimer's disease (AD).

METHODS

Amyloid precursor protein (APP)-23 mice were housed under standard or enriched conditions or in cages equipped with a running wheel. We assessed beta-amyloid plaque load, adult hippocampal neurogenesis, spatial learning, and mRNA levels of trophic factors in the brain.

RESULTS

Despite stable beta-amyloid plaque load, enriched-living mice showed improved water maze performance, an up-regulation of hippocampal neurotrophin (NT-3) and brain-derived neurotrophic factor (BDNF) and increased hippocampal neurogenesis. In contrast, despite increased bodily fitness, wheel-running APP23 mice showed no change in spatial learning and no change in adult hippocampal neurogenesis but a down-regulation of hippocampal and cortical growth factors.

CONCLUSIONS

We conclude that structural and molecular prerequisites for activity-dependent plasticity are preserved in mutant mice with an AD-like pathology. Our study might help explain benefits of activity for the aging brain but also demonstrates differences between physical and more cognitive activity. It also suggests a possible cellular correlate for the dissociation between structural and functional pathology often found in AD.

Embryonic spinal motor neurons are thought to depend for survival on unidentified factors secreted both by their peripheral targets and by cells within the central nervous system. The neurotrophins are a family of polypeptides required for survival of discrete central and peripheral neuronal populations in vivo and in vitro. In spite of their ability to reduce motor neuron death in vivo, the known neurotrophins have been thought to be without direct effect on motor neurons. Here we show that picomolar concentrations of three of them, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-5, can prevent the death of cultured embryonic rat spinal motor neurons. Furthermore, messenger RNA coding for neurotrophins is present at appropriate stages in spinal cord and limb bud, and mRNA for their receptors is found in motor neurons. These neurotrophins may therefore be physiological motor neuron growth factors.