A rapid and simple procedure is presented to obtain nearly pure populations of human neuron-like cells from the SH-SY5Y neuroblastoma cell line. Sequential exposure of SH-SY5Y cells to retinoic acid and brain-derived neurotrophic factor in serum-free medium yields homogeneous populations of cells with neuronal morphology, avoiding the presence of other neural crest derivatives that would normally arise from those cells. Cells are withdrawn from the cell cycle, as shown by 5-bromo-2'-deoxyuridine uptake and retinoblastoma hypophosphorylation. Cell survival is dependent on the continuous presence of brain-derived neurotrophic factor, and removal of this neurotrophin causes apoptotic cell death accompanied by an attempt to reenter the cell cycle. Differentiated cells express neuronal markers, including neurofilaments, neuron-specific enolase, and growth-associated protein-43 as well as neuronal polarity markers such as tau and microtubule-associated protein 2. Moreover, differentiated cultures do not contain glial cells, as could be evidenced after the negative staining for glial fibrillary acidic protein. In conclusion, the protocol presented herein yields homogeneous populations of human neuronal differentiated cells that present many of the characteristics of primary cultures of neurons. This model may be useful to perform large-scale biochemical and molecular studies due to its susceptibility to genetic manipulation and the availability of an unlimited amount of cells.

For survival, embryonic motoneurons in vertebrates depend on as yet undefined neurotrophic factors present in the limb bud. Members of the neurotrophin family are currently the best candidates for such neurotrophic factors, but inactivation of their receptor genes leads to only partial loss of motoneurons, which suggests that other factors are involved. Glial cell line-derived neurotrophic factor (GDNF), originally identified as a trophic factor specific for dopaminergic neurons, was found to be 75-fold more potent than the neurotrophins in supporting the survival of purified embryonic rat motoneurons in culture. GDNF messenger RNA was found in the immediate vicinity of motoneurons during the period of cell death in development. In vivo, GDNF rescues and prevents the atrophy of facial motoneurons that have been deprived of target-derived survival factors by axotomy. GDNF may therefore be a physiological trophic factor for spinal motoneurons. Its potency and specificity in vitro and in vivo also make it a good candidate for treatment of motoneuron disease.

The brain-derived neurotrophic factor (BDNF) has been involved in pre- and postnatal brain development. Moreover, abundant levels of this neurotrophin have been found in animal and human brain and serum. This study was aimed to assess the postnatal change profile of both serum and brain BDNF levels. By using immunoassay and reverse transcription-polymerase chain reaction methods, BDNF protein and mRNA levels were determined in serum and platelets, respectively, and in two brain structures (hippocampus and frontal cortex) of postnatal rats (one and three weeks old), young adults (two months old) and in aged animals (two years old). The results showed that brain and serum BDNF levels underwent similar changes during maturation and aging processes (analysis of variance (ANOVA): P<0.001, P<0.001, for hippocampus and serum, respectively). During the same investigation period, the measure of BDNF mRNA indicated gradual changes in the hippocampus but not in platelets (ANOVA: P<0.001 and not significant, for hippocampus and platelets, respectively). Interestingly, there was a positive correlation between serum and cortical BDNF levels (r=0.81, P<0.01), especially in young animals. This study of ontogenic characteristics of BDNF in blood and central nervous system can help to shed more light on the role of platelet BDNF.

To obtain insight into the site and stage specificity of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) action in vivo, we compared the expression patterns of the genes for these three related neurotrophic factors as well as for the NGF receptor in developing and adult rats. Initial embryonic expression of these related neurotrophic factors approximately coincides with the onset of neurogenesis. However, the levels at which the three factors are expressed at this time and throughout the developing nervous system are dramatically different. NT-3 is by far the most highly expressed in immature regions of the CNS in which proliferation, migration, and differentiation of neuronal precursors is ongoing. NT-3 expression dramatically decreases with maturation of these regions. By contrast, BDNF expression is low in developing regions of the CNS and increases as these regions mature. NGF expression varies during the development of discrete CNS regions, but not in any consistent manner compared with NT-3 and BDNF. Despite the dramatic variations, NT-3, BDNF, and NGF do share one striking similarity--high level expression in the adult hippocampus. Our observations are consistent with the idea that NT-3, BDNF, and NGF have paralleled as well as reciprocal roles in vivo.

Nerve growth factor (NGF) and other neurotrophins support survival of neurons through processes that are incompletely understood. The transcription factor CREB is a critical mediator of NGF-dependent gene expression, but whether CREB family transcription factors regulate expression of genes that contribute to NGF-dependent survival of sympathetic neurons is unknown. CREB-mediated gene expression was both necessary for NGF-dependent survival and sufficient on its own to promote survival of sympathetic neurons. Moreover, expression of Bcl-2 was activated by NGF and other neurotrophins by a CREB-dependent transcriptional mechanism. Overexpression of Bcl-2 reduced the death-promoting effects of CREB inhibition. Together, these data support a model in which neurotrophins promote survival of neurons, in part through a mechanism involving CREB family transcription factor-dependent expression of genes encoding prosurvival factors.

Fear is an adaptive component of the acute "stress" response to potentially-dangerous (external and internal) stimuli which threaten to perturb homeostasis. However, when disproportional in intensity, chronic and/or irreversible, or not associated with any genuine risk, it may be symptomatic of a debilitating anxious state: for example, social phobia, panic attacks or generalized anxiety disorder. In view of the importance of guaranteeing an appropriate emotional response to aversive events, it is not surprising that a diversity of mechanisms are involved in the induction and inhibition of anxious states. Apart from conventional neurotransmitters, such as monoamines, gamma-amino-butyric acid (GABA) and glutamate, many other modulators have been implicated, including: adenosine, cannabinoids, numerous neuropeptides, hormones, neurotrophins, cytokines and several cellular mediators. Accordingly, though benzodiazepines (which reinforce transmission at GABA(A) receptors), serotonin (5-HT)(1A) receptor agonists and 5-HT reuptake inhibitors are currently the principle drugs employed in the management of anxiety disorders, there is considerable scope for the development of alternative therapies. In addition to cellular, anatomical and neurochemical strategies, behavioral models are indispensable for the characterization of anxious states and their modulation. Amongst diverse paradigms, conflict procedures--in which subjects experience opposing impulses of desire and fear--are of especial conceptual and therapeutic pertinence. For example, in the Vogel Conflict Test (VCT), the ability of drugs to release punishment-suppressed drinking behavior is evaluated. In reviewing the neurobiology of anxious states, the present article focuses in particular upon: the multifarious and complex roles of individual modulators, often as a function of the specific receptor type and neuronal substrate involved in their actions; novel targets for the management of anxiety disorders; the influence of neurotransmitters and other agents upon performance in the VCT; data acquired from complementary pharmacological and genetic strategies and, finally, several open questions likely to orientate future experimental- and clinical-research. In view of the recent proliferation of mechanisms implicated in the pathogenesis, modulation and, potentially, treatment of anxiety disorders, this is an opportune moment to survey their functional and pathophysiological significance, and to assess their influence upon performance in the VCT and other models of potential anxiolytic properties.

Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the success of these approaches depends on an in-depth understanding of the mechanisms that lead to RGC dysfunction and death. In recent years, there has been an exponential increase in valuable information regarding the molecular basis of RGC death stemming from animal models of acute and chronic optic nerve injury as well as experimental glaucoma. The emerging landscape is complex and points at a variety of molecular signals - acting alone or in cooperation - to promote RGC death. These include: axonal transport failure, neurotrophic factor deprivation, toxic pro-neurotrophins, activation of intrinsic and extrinsic apoptotic signals, mitochondrial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity. Collectively, this body of work has considerably updated and expanded our view of how RGCs might die in glaucoma and has revealed novel, potential targets for neuroprotection.

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family of neurotrophins, has central roles in the development, physiology, and pathology of the nervous system. We have elucidated the structure of the human BDNF gene, identified alternative transcripts, and studied their expression in adult human tissues and brain regions. In addition, the transcription initiation sites for human BDNF transcripts were determined and the activities of BDNF promoters were analyzed in transient overexpression assays. Our results show that the human BDNF gene has 11 exons and nine functional promoters that are used tissue and brain-region specifically. Furthermore, noncoding natural antisense RNAs that display complex splicing and expression patterns are transcribed in the BDNF gene locus from the antiBDNF gene (approved gene symbol BDNFOS). We show that BDNF and antiBDNF transcripts form dsRNA duplexes in the brain in vivo, suggesting an important role for antiBDNF in regulating BDNF expression in human.

Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice. Neuronal Fndc5 gene expression is regulated by PGC-1α, and Pgc1a(-/-) mice show reduced Fndc5 expression in the brain. Forced expression of FNDC5 in primary cortical neurons increases Bdnf expression, whereas RNAi-mediated knockdown of FNDC5 reduces Bdnf. Importantly, peripheral delivery of FNDC5 to the liver via adenoviral vectors, resulting in elevated blood irisin, induces expression of Bdnf and other neuroprotective genes in the hippocampus. Taken together, our findings link endurance exercise and the important metabolic mediators, PGC-1α and FNDC5, with BDNF expression in the brain.

The neurotrophins are growth factors that play critical roles in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases and the p75 neurotrophin receptor (p75NTR). While the Trk receptors are responsible for most of the survival and growth properties of the neurotrophins, the actions of p75NTR fall into two categories. First, p75NTR is a Trk co-receptor that can enhance or suppress neurotrophin-mediated Trk receptor activity. Second, p75NTR autonomously activates signaling cascades that result in the induction of apoptosis or in the promotion of survival. The signaling cascades activated by p75NTR remain elusive, but structural and functional differences between p75NTR and other tumor necrosis factor receptor (TNFR) superfamily members suggest that p75NTR employs distinct signaling pathways. p75NTR has been shown to activate the NF-kappaB, Akt, and JNK pathways and interacts with several adaptor proteins. Of these, NRAGE, NADE, and NRIF have been associated with the induction of apoptosis, and FAP-1, RIP2, and TRAF6 appear to promote cellular survival. It remains a major challenge to link the various p75NTR binding proteins to specific p75NTR-dependent functions, but the identification of p75NTR interactors and signaling pathways has sparked new directions in p75NTR research, and will provide a better understanding of this enigmatic receptor.

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.

Homologous recombination was utilized to generate mice with a deletion in the coding sequence of the nerve growth factor (NGF) gene. Animals homozygous for NGF disruption failed to respond to noxious mechanical stimuli, and histological analysis revealed profound cell loss in both sensory and sympathetic ganglia. Within dorsal root ganglia, effects of the mutation appeared to be restricted to small and medium peptidergic neurons. These observations confirm the critical dependence of sensory and sympathetic neurons on NGF and demonstrate that other neurotrophins are not able to compensate for the loss of NGF action on these cells. Examination of the central nervous system revealed that, in marked contrast with neurons of sensory and sympathetic ganglia, basal forebrain cholinergic neurons differentiate and continue to express phenotypic markers for the life span of the null mutant mice. Thus, differentiation and initial survival of central NGF-responsive neurons can occur in the absence of NGF.

Vesicular pathways coupling the neuromuscular junction with the motor neuron soma are essential for neuronal function and survival. To characterize the organelles responsible for this long-distance crosstalk, we developed a purification strategy based on a fragment of tetanus neurotoxin (TeNT H(C)) conjugated to paramagnetic beads. This approach enabled us to identify, among other factors, the small GTPase Rab7 as a functional marker of a specific pool of axonal retrograde carriers, which transport neurotrophins and their receptors. Furthermore, Rab5 is essential for an early step in TeNT H(C) sorting but is absent from axonally transported vesicles. Our data demonstrate that TeNT H(C) uses a retrograde transport pathway shared with p75(NTR), TrkB, and BDNF, which is strictly dependent on the activities of both Rab5 and Rab7. Therefore, Rab7 plays an essential role in axonal retrograde transport by controlling a vesicular compartment implicated in neurotrophin traffic.

The neurons of the cochlear ganglion transmit acoustic information between the inner ear and the brain. These placodally derived neurons must produce a topographically precise pattern of connections in both the inner ear and the brain. In this review, we consider the current state of knowledge concerning the development of these neurons, their peripheral and central connections, and their influences on peripheral and central target cells. Relatively little is known about the cellular and molecular regulation of migration or the establishment of precise topographic connection to the hair cells or cochlear nucleus (CN) neurons. Studies of mice with neurotrophin deletions are beginning to yield increasing understanding of variations in ganglion cell survival and resulting innervation patterns, however. Finally, existing evidence suggests that while ganglion cells have little influence on the differentiation of their hair cell targets, quite the opposite is true in the brain. Ganglion cell innervation and synaptic activity are essential for normal development of neurons in the cochlear nucleus.

Converging lines of research suggest that the hippocampal complex (HC) may have a role in the pathophysiology of major depressive disorder (MDD). Although postmortem studies show little cellular death in the HC of depressed patients, animal studies suggest that elevated glucocorticoid levels associated with MDD may negatively affect neurogenesis, cause excitotoxic damage or be associated with reduced levels of key neurotrophins in the HC. Antidepressant medications may counter these effects, having been shown to increase HC neurogenesis and levels of brain-derived neurotrophic factor in animal studies. Neuropsychological studies have identified deficits in hippocampus-dependent recollection memory that may not abate with euthymia, and such memory impairment has been the most reliably documented cognitive abnormality in patients with MDD. Finally, data from imaging studies suggest both structural changes in the volume of the HC and functional alterations in frontotemporal and limbic circuits that may be critical for mood regulation. The extent to which such functional and structural changes determine clinical outcome in MDD remains unknown; a related, but also currently unanswered, question is whether the changes in HC function and structure observed in MDD are preventable or modifiable with effective treatment for the depressive illness.

Brain-derived neurotrophic factor (BDNF) is a prototypic neurotrophin that regulates diverse developmental events from the selection of neural progenitors to the terminal dendritic differentiation and connectivity of neurons. We focus here on activity-dependent synaptic regulation by BDNF and its receptor, full length TrkB. BDNF-TrkB signaling is involved in transcription, translation, and trafficking of proteins during various phases of synaptic development and has been implicated in several forms of synaptic plasticity. These functions are carried out by a combination of the three signaling cascades triggered when BDNF binds TrkB: The mitogen-activated protein kinase (MAPK), the phospholipase Cgamma (PLC PLCgamma), and the phosphatidylinositol 3-kinase (PI3K) pathways. MAPK and PI3K play crucial roles in both translation and/or trafficking of proteins induced by synaptic activity, whereas PLCgamma regulates intracellular Ca(2+) that can drive transcription via cyclic AMP and a protein kinase C. Conversely, the abnormal regulation of BDNF is implicated in various developmental and neurodegenerative diseases that perturb neural development and function. We will discuss the current state of understanding BDNF signaling in the context of synaptic development and plasticity with a focus on the postsynaptic cell and close with the evidence that basic mechanisms of BDNF function still need to be understood to effectively treat genetic disruptions of these pathways that cause devastating neurodevelopmental diseases.

We have tested the role of glial cell line-derived neurotrophic factor (GDNF) in regulating a group of putatively nociceptive dorsal root ganglion (DRG) neurons that do not express calcitonin gene-related peptide (CGRP) and that downregulate the nerve growth factor (NGF) receptor tyrosine kinase, TrkA, after birth. We show that mRNA and protein for the GDNF receptor tyrosine kinase, Ret, are expressed in the DRG in patterns that differ markedly from those of any of the neurotrophin receptors. Most strikingly, a population of small neurons initiates expression of Ret between embryonic day 15.5 and postnatal day 7.5 and maintains Ret expression into adulthood. These Ret-expressing small neurons are selectively labeled by the lectin IB4 and project to lamina IIi of the dorsal horn. Ret-expressing neurons also express the glycosyl-phosphatidyl inositol-linked (GPI-linked) GDNF binding component GDNFR-alpha and retrogradely transport 125I-GDNF, indicating the presence of a biologically active GDNF receptor complex. In vitro, GDNF supports the survival of small neurons that express Ret and bind IB4 while failing to support the survival of neurons expressing TrkA and CGRP. Together, our findings suggest that IB4-binding neurons switch from dependence on NGF in embryonic life to dependence on GDNF in postnatal life and are likely regulated by GDNF in maturity.

Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. beta-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy.

Neuregulins and their specific receptors, members of the ErbB family of tyrosine kinases, have been implicated in the control of growth and development of Schwann cells, specialized cells that wrap around nerve axons to provide electrical insulation. Here we use gene targeting to generate mice that lack ErbB3, a high-affinity neuregulin receptor. Homozygous erbB3 mutant embryos lack Schwann-cell precursors and Schwann cells that accompany peripheral axons of sensory and motor neurons. The initial development of motor neurons and sensory neurons of dorsal root ganglia occurs as it should, but at later stages most motor neurons (79%) and sensory neurons in dorsal root ganglia (82%) undergo cell death in erbB3 mutant embryos. Degeneration of the peripheral nervous system in erbB3 mutant pups is thus much more severe than the cell death in mice that lack neurotrophins or neurotrophin receptors. We also show that ErbB3 functions in a cell-autonomous way during the development of Schwann cells, but not in the survival of sensory or motor neurons. Our results indicate that sensory and motor neurons require factors for their survival that are provided by developing Schwann cells.

Amyloid-β (Aβ) peptides, derived from the amyloid precursor protein, and the microtubule-associated protein tau are key pathogenic factors in Alzheimer's disease (AD). How exactly they impair cognitive functions is unknown. We assessed the effects of Aβ and tau on axonal transport of mitochondria and the neurotrophin receptor TrkA, cargoes that are critical for neuronal function and survival and whose distributions are altered in AD. Aβ oligomers rapidly inhibited axonal transport of these cargoes in wild-type neurons. Lowering tau levels prevented these defects without affecting baseline axonal transport. Thus, Aβ requires tau to impair axonal transport, and tau reduction protects against Aβ-induced axonal transport defects.

This review highlights recent evidence from clinical and basic science studies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimer's disease and schizophrenia, and may also enhance recovery from traumatic neurological injury such as stroke. Recent basic science studies show that not only does exogenous estradiol decrease the response to various forms of insult, but the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Thus, our view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission and enhanced neurogenesis. Some of the mechanisms underlying these effects are independent of the classically defined nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the classical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades through direct interactions with protein kinases or that estrogen receptor signaling may converge with signaling by other trophic molecules to confer resistance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include the optimal ligand and doses that can be used clinically to confer benefit without undue risk, modulation of neurotrophin and neurotrophin receptor expression, interaction of estrogen with regulated cofactors and coactivators that couple estrogen receptors to basal transcriptional machinery, interactions of estrogen with other survival and regeneration promoting factors, potential estrogenic effects on neuronal replenishment, and modulation of phenotypic choices by neural stem cells.

In a manner unique among activity-regulated immediate early genes (IEGs), mRNA encoded by Arc (also known as Arg3.1) undergoes rapid transport to dendrites and local synaptic translation. Despite this intrinsic appeal, relatively little is known about the neuronal and behavioral functions of Arc or its molecular mechanisms of action. Here, we attempt to distill recent advances on Arc spanning its transcriptional and translational regulation, the functions of the Arc protein in multiple forms of neuronal plasticity [long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity], and its broader role in neural networks of behaving animals. Worley and colleagues have shown that Arc interacts with endophilin and dynamin, creating a postsynaptic trafficking endosome that selectively modifies the expression of AMPA-type glutamate receptors at the excitatory synapses. Both LTD and homeostatic plasticity in the hippocampus are critically dependent on Arc-mediated endocytosis of AMPA receptors. LTD evoked by activation of metabotropic glutamate receptors depends on rapid Arc translation controlled by elongation factor 2. Bramham and colleagues have shown that sustained translation of newly induced Arc mRNA is necessary for cofilin phosphorylation and stable expansion of the F-actin cytoskeleton underlying LTP consolidation in the dentate gyrus of live rats. In addition to regulating F-actin, Arc synthesis maintains the activity of key translation factors during LTP consolidation. This process of Arc-dependent consolidation is activated by the secretory neurotrophin, BDNF. Moore and colleagues have shown that Arc mRNA is a natural target for nonsense-mediated mRNA decay (NMD) by virtue of its two conserved 3'-UTR introns. NMD and other related translation-dependent mRNA decay mechanisms may serve as critical brakes on protein expression that contribute to the fine spatial-temporal control of Arc synthesis. In studies in behaving rats, Guzowski and colleagues have shown that location-specific firing of CA3 and CA1 hippocampal neurons in the presence of theta rhythm provides the necessary stimuli for activation of Arc transcription. The impact of Arc transcription in memory processes may depend on the specific context of coexpressed IEGs, in addition to posttranscriptional regulation of Arc by neuromodulatory inputs from the amygdala and other brain regions. In sum, Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to diverse forms of synaptic plasticity, thereby optimizing information storage in active networks.

Macrophage/microglia (M phi) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood-brain barrier, behave as one of the immune effector cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M phi, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS). HAD primarily involves subcortical gray matter, and both HAD and MS affect sub-cortical white matter. AD is a cortical disease. The process of M phi and astrocytes activation leading to neurotoxicity share similarities among the three diseases. Human Immunodeficiency Virus (HIV)-1-infected M phi are involved in the pathogenesis of HAD and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). In AD, M phis produce these molecules and are activated by beta-amyloid proteins and related oligopeptides. Demyelination in MS involves M phi that become lipid laden, spurred by several possible antigens. In these three diseases, cytokine/chemokine communications between M phi and astrocytes occur and are involved in the balance of protective and destructive actions by these cells. This review describes the role of M phi and astrocytes in the pathogenesis of these three progressive neurological diseases, examining both beneficent and deleterious effects in each disease.

Neurotrophins are a unique family of polypeptide growth factors that influence the proliferation, differentiation, survival and death of neuronal and non-neuronal cells. They are essential for the health and well-being of the nervous system. NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophin-3) and NT-4 (neurotrophin-4) also mediate additional higher-order activities, such as learning, memory and behaviour, in addition to their established functions for cell survival. The effects of neurotrophins depend upon their levels of availability, their affinity of binding to transmembrane receptors and the downstream signalling cascades that are stimulated after receptor activation. Alterations in neurotrophin levels have been implicated in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, as well as psychiatric disorders, including depression and substance abuse. Difficulties in administering trophic factors have led to the consideration of using small molecules, such as GPCR (G-protein-coupled receptor) ligands, which can participate in transactivation events. In this review, we consider the signalling pathways activated by neurotrophins in both health and disease states.