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A REVIEW ON BDNF AND NEURONAL PLASITICITY Rajvi Shah*, Jigna Shah Department of Pharmacology, Shri Sarvajanik Pharmacy College, Near Arvind Baug, Mehsana-384 001, Gujarat, India. For Correspondence*: Rajvi Shah Shri Sarvajanik Pharmacy College, Near Arvind Baug, Mehsana, Gujarat, India. Contact no.: +919898780373 Email: [email protected] INTRODUCTION The family of neurotrophins comprises four structurally related proteins, namely the nerve growth factor (NGF), the Brain-Derived Neurotrophic Factor (BDNF), and the neurotrophins 3 and neurotrophins 4/5 (NT3 and NT4/5). A common feature of gene organization in this family is the existence of a single coding exon which expression is complicated by promoter multiplicity and transcript diversity1. BDNF is found in most vertebrate classes including bony fishes, amphibians, reptiles, birds and mammals. A common feature of gene organization in this family is the existence of a single coding exon which expression is complicated by promoter multiplicity and transcript diversity1. Neurotrophins are synthesized as precursors of 30-35 kDa, and then proteolytically processed, either intra cellularly by furin or prohormone convertases, or extracellularly by plasmin or metalloproteases, at the level of a highly conserved dibasic amino acid motif. These types of proteins have similar numbers of amino acid, isoelectric points (9-10 range) and having 50% identity in the primary structure. Neutrophines having common structure with variable domains determine to bind their specific receptor. All of these factors thus bind to p75NGFR receptors but selectively interact with their individual high-affinity protein kinase receptors of the trk (tropomyosine-related kinase) family. NGF mediates its effect via TrkA, BDNF, and NT-4 via TrkB, while NT-3 interacts mainly with TrkC and also at lower affinity with TrkB receptors. The ability of Trk and p75NGFR receptors to present different binding sites and affinity to each individual neurotrophin seems to be an important element that determines the type of biological response2. Trks are transmembrane tyrosine kinase receptors with conserved intracellular domains that mediate several well-characterized signaling pathways, including those controlled by Ras, the Cdc42/Rac/RhoG protein family, MAPK, PI3K, and PLC-gama3. Trk receptors have a broad range of splice variants and several of them produce significant changes in the structure of the encoded proteins. BNDF acts in a paracrine and autocrine manner to control a variety of brain processes, including the growth, development, differentiation and maintenance of neuronal systems, neuronal plasticity, synaptic activity and neurotransmitter-mediated activities4. MECHANISM OF ACTION OF BDNF GENE BDNF has an extremely complex genomic structure. The human gene presents eleven exons and nine functional promoters, producing up to seventeen different transcripts which encode for the same protein. In the rat, Bdnf gene has nine exons with its own promoter, producing nine different transcripts. Complex set of genomic promoters is thought to mediate accurate control of BDNF production. Cumulative evidence indicates that these transcripts are differentially distributed across brain regions in different cell types and even within different parts of the neuron. For example, in the rat, exon III transcripts are detected only in cell bodies, whereas exon IV transcripts are found in cell bodies and dendritic processes of visual cortex neurons. These promoters are differentially activated in response to diverse and varied signaling events, including epigenetic regulation. The BDNF messenger RNA (mRNA) expression is reduced in peripheral blood mononuclear cells of patients with major depression. This alteration of BDNF mRNA expression was more pronounced in recent suicide attempters. BDNF transcripts are translated into pro-BDNF, which binds to sortilin in the golgi to facilitate its appropriate folding, trafficking and secretion. Single nucleotide polymorphism in the BDNF gene, substitution of a valine for a methionine at the codon 66 (val66met), is involved in altered trafficking of BDNF. Such change seems to take place due to a reduced interaction of BDNF and sortilin inducing metBDNF aggregation to the cell body of neurons and thus preventing it to interact with synaptophysin. That would in turn reduce the BDNF secretion into the synapse4. DISTRIBUTION IN THE CNS Regional distribution BDNF was discovered in 1982, a number of studies have analyzed its localization and distribution in the CNS, using antibodies recognizing different BDNF epitopes and giving rise to sometimes contrasting findings. This is thought to be due to antibody specificity for epitopes that are only available before complete BDNF folding or are masked by the interaction of BDNF with different intracellular proteins in different sub cellular compartments. The analysis of BDNF distribution is also complicated by the fact that extracellular BDNF is internalized by neurons, antero or retrogradely transported and rapidly secreted, thus leading to the detection of low protein levels in the cell body. It may also be present in a poor unfolded state that may prevent antibody recognition. Despite these technical problems (which can be overcome by also looking at the distribution of BDNF mRNA), it has been found that BDNF protein is widely distributed in the CNS, with higher levels in the cerebral cortex, basal forebrain, striatum, hippocampus, hypothalamus, brainstem and cerebellum. Analyses of BDNF distribution in adult brain have revealed high levels of BDNF mRNA and protein in rodent and human cerebral cortex. BDNF protein immunoreactivity is preferentially found in neurons with a pyramidal morphology in all cortical regions examined, including the primary visual cortex and other occipital areas, the motor and somatosensory cortex, the insular cortex, and the cortex of the temporal pole. In humans and rat, pyramidal BDNF-immunoreactive neurons are preferentially located in layers V–VI and II–III, and seem to be more abundant in some cortical regions (frontal, parietal and temporal cortex) than others (primary motor and sensory cortices). Some comparative studies of cellular BDNF mRNA and protein levels have revealed BDNF-labeled neurons in the striatum, but many others have reported a lack of BDNF mRNA in this brain region. Consistently, low levels of striatal BDNF mRNA have been demonstrated in the rodent striatum, and only become evident after a seizure. In humans, BDNF immunoreactive neuronal cell bodies have rarely been found in the striatum; in particular, nonhomogeneous BDNF staining has been observed in the caudate nucleus, putamen and nucleus accumbens. BDNF immunoreactivity and BDNF mRNA expression have also been observed in mammalian nigral dopaminergic neurons projecting to striatal targets. The BDNF in nigral cells mainly comes from mesencephalic dopaminergic neurons, because specific lesions of mesencephalic dopaminergic neurons decrease nigral BDNF mRNA however, they cause a very small variation in the amount of striatal BDNF once again confirming that most striatal BDNF is of cortical origin. Cellular distribution A number of studies indicate that BDNF is mainly present in neurons, but early works indicated that glial cells could also express BDNF under conditions of severe metabolic stress have reported the presence of BDNF-immunoreactive oligodendrocytes in rat brain white matter, and more recent studies have shown that microglia in vitro secrete a limited amount of BDNF. Although BDNF synthesis has been reported in glial cells, the most popular hypothesis is that most of the BDNF found in glial cells is internalized, as is suggested by the presence of receptorbound BDNF on their plasma membrane. It has been found that glial cells express the truncated and catalytic forms of TrkB which mediates exogenous BDNF internalization and storage, thus indicating that astrocytes and other cells expressing the truncated form of TrkB may regulate the local bioavailability of BDNF when glial cells are activated by endogenous or exogenous stimuli. Subcellular distribution Early data indicated the presence of BDNF in the nuclei, cell body, cytoplasm and dendrites of neurons, and suggested that pro-BDNF is processed differentially, giving rise to a mature secretory form or an alternative product that is translocated to the nucleus where it influences transcription in vivo. Some later studies confirmed the presence of nuclear BDNF; however, others did not (probably because of differences in the antibodies used). BDNF AND VARIOUS RECEPTORS Regulation of BDNF expression by glutamate As a major excitatory neurotransmitter system in the brain, glutamate is a key element regulating activity-dependent BDNF mRNA expression in neurons. In vivo and in vitro both activation of different subtypes of ionotropic glutamate receptor by a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate (KA), and N-methyl-D-aspartic acid (NMDA) trigger significant up regulation of BDNF mRNA expression. While the majority of previous studies have been focused on its expression in forebrain regions, less information is available about BDNF mRNA expression regulation in the cerebellum. BDNF mRNA is highly expressed in cerebellar granule neurons and less in Purkinje cells6. Corresponding to late development of the cerebellum, BDNF expression in the cerebellum is not apparent until postnatal day 15 (P15), peaks around P20, and maintains at high level through adulthood in rodents6. Severe deficiencies in motor coordination seen in BDNF knockout mice have been linked to abnormal cerebellar development7. However, the high early postnatal mortality and the universal deletion of the BDNF gene significantly limit the usefulness of this genetic model. Regulation of BDNF expression by GABA It the central nervous system, BDNF expression is substantially increased by manipulations stimulating neuronal activity9 which seems to be mediated by glutamate. We have also shown that glutamate stimulates BDNF mRNA and peptide expression in hypothalamic neurons in primary culture 11. In other structures such as neocortex, hippocampus or spinal cord8, GABA antagonists and agonists are known to regulate BDNF expression through activation of different receptor subtypes. Glutamic acid and gamma-aminobutyric acid (GABA) are major excitatory and inhibitory synaptic neurotransmitters, respectively, in the vertebrate central nervous system. In addition, both neurotransmitters are known to be located in the hypothalamus, where they control the synthesis of various neurohormones10. An appropriate balance between the effects of these neurotransmitter systems is essential to ensure normal neuronal function and preservation of homeostasis and endocrine adaptation. Regulation of BDNF expression by serotonin Serotonin reuptake inhibitors in particular and antidepressants in general, act by evoking adaptive changes in extracellular signaling and subsequently, postsynaptic signal transduction and gene expression. In particular, studies have linked chronic antidepressant treatment with changes in the expression of the neuronal trophin, brain-derived neurotrophic factor12. For example, Nibuya et al. found that chronic treatment of rats with a variety of antidepressants (SRIs, tricyclics, monoamine oxidase inhibitors and atypical antidepressants) elevates BDNF mRNA in hippocampal and cortical brain regions13. Neurotrophic factors are endogenous soluble proteins that regulate the survival, growth, morphological plasticity, and synthesis of new neurons for differentiated function. The neurotrophin family in mammals is composed of four known proteins: BDNF, nerve growth factor, neurotrophin-3 and neurotrophin-4. BDNF is a 27 kDa homodimeric. In addition to acting as a trophic factor BDNF is thought to modulate other signaling molecules including the monoamine, amino acid and peptide neurotransmitters14. Indirect evidence suggests that BDNF can augment serotonergic neurotransmission BDNF infused directly into the brain is known to influence the survival and function of serotonergic neurons, affect the turnover ratio of 5-HT versus its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) and potentiate activity-dependent release of 5-HT15. Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging 35. Regulation of BDNF expression by acetylcholine Cholinergic innervations from the medial septal nucleus seem to regulate BDNF mRNA expression in the hippocampus. Stimulation of this pathway increased BDNF and NGF mRNAs16. By contrast, transaction of Wmbria fornix, which conveys cholinergic axons projecting from the septum to the hippocampus, reduces BDNF and NGF mRNA levels in the hippocampus17. Both nicotinic and muscarinic receptors seem to be involved in acetylcholine regulation of BDNF expression. Characterization of cholinergic receptors involved in NGF and BDNF mRNA, and NGF protein up-regulation in the rat hippocampus indicated the participation of muscarinic receptors18. In addition, acute nicotine administration decreased and chronic nicotine administration increased BDNF mRNA expression in the hippocampus. Since it has been reported19 that chronic nicotine treatment decreases hippocampal 5-HT overflow the chronic nicotine effect on BDNF could be mediated by a decrease in 5-HT2A receptor activation. Besides, administration of the muscarinic agonist pilocarpine to rats strongly increases BDNF and NGF mRNA expression without affecting NT-3 mRNA20. REGULATION OF BDNF EXPRESSION IN THE CNS BY PERIPHERAL HORMONES Estrogen and testosterone It has been reported that levels of BDNF mRNA fluctuated significantly during the estrous cycle in CA1, CA3, and CA4 areas of the hippocampus. The highest levels were detected on the morning of diestrus 2, when progesterone levels are relatively low, and the lowest levels were detected on the afternoon of pro-estrus, when progesterone levels were highest21. Some authors also demonstrated that estrogens regulate BDNF mRNA and BDNF peptide in the rat hippocampus during development. Estrogens, similar to BDNF, have been shown to enhance LTP22 and may regulate neural processes underlying learning and memory. The mechanisms are unknown, but one possibility could be through BDNF gene regulation since a putative estrogenresponsive element has been localized on the BDNF gene. In addition, estrogen and neurotrophins share some signaling pathways23 which could partially explain some of the trophic estrogen effects on neurite growth and differentiation. Testosterone has been shown to regulate BDNF mRNA levels in avian hypothalamic slice cultures. In addition, in the adult canary brain, BDNF is present in the high vocal center (HVC, a forebrain nucleus involved in songbird song system) in males but not in females24. Regulation by glucocorticoids Glucocorticoids thus trigger an inverted dose-response effect on BDNF expression, which could be explained by the presence, in the hippocampus, of the two types of receptors activated by corticosterone, type I or mineralocorticoid (MR) and type II or glucocorticoid (GR) receptors. However, BDNF mRNA expression in the dorsal hippocampus and the neocortex of the rat appears to negatively depend on both receptors25. Adrenal steroid hormones can regulate gene expression at the DNA level by binding to glucocorticoid-response elements in promoter regions. So far no classical GRE consensus sequences have been identified in BDNF promoters, but indirect effects on other transcription factors regulating BDNF gene expression cannot be excluded. Regulation by thyroid hormones As thyroid hormones are known to play a crucial role in the development and maturation of the nervous system and to contribute to plasticity processes in the adult brain, studies were undertaken to investigate its possible regulation of neurotrophins. The results are extremely controversial, thus making it difficult to draw a clear conclusion on thyroid hormones effects on neurotrophins. For example, hypothyroidism was found to decrease trk mRNA levels in the striatum at different stages of development as well as in adult animals26. PATHOLOGIES BDNF and Depression Depression is one of the most frequent of mood disorders by which the dysfunction of neuroplasticity or remodeling play a significant role. This hypothesis is supported by preclinical and clinical investigations demonstrating that stress and depression lead to reduction of the total volume of the hippocampus and to cell loss in the limbic system. The proposed cell death mechanisms of depression include the impairment of neurotrophic mechanism, elevated glucocorticoid and excitatory neurotransmitter levels, glial cell changes and the secondary suppression of neurogenesis. According to the neurotrophin hypothesis of depression, brainderived neurotrophic factor (BDNF) is of major importance because it modulates the plasticity, inhibits cell death cascades and increases cell survival proteins that are responsible for proliferation and maintenance of central nervous system neurons. This was suggested by studies indicating that depressive states in animal models are associated with reduced BDNF levels in the brain, and central administration of BDNF reverse such depressive states27. BDNF and Epilepsy Seizure induced increases in BDNF mRNA levels were transient, whereas the increase in BDNF protein content persisted longer-over 4 days in the hippocampus and entorhinal cortex/amygdalethan in frontal cortex or cerebellum28. Importantly, seizures also seem to induce messengers that encode neurotrophin receptors29, 30. BDNF and Parkinson’s disease Parkinson’s disease (PD) is characterized by the selective and progressive loss of dopaminergic neurons of the substance nigra. This is followed by subsequent depletion of striatal dopamine, which leads to motor dysfunction since these neurons project to the striatum31. Circadian rhythm of BDNF and its transcripts The suprachiasmatic nucleus (SCN) of the hypothalamus contains an endogenous oscillator that is the primary biological clock in mammals32. Although the mechanisms underlying endogenous clock rhythmicity are not yet fully characterized, it is known that a number of genes oscillate in a circadian fashion. Relatively recent findings suggest that some neurotrophins may be involved in the light-regulated circadian pacemaker of the SCN33, 34. CONCLUSION Neural plasticity seems to be defected in patients and responsible for the cognitive decline observed in various type of patients .BDNF is crucially disturbed in brain and form an important signaling pathway influencing neural plasticity and neural network status. Proper reinforcing of the important signaling pathway could be promising approach for therapeutic interventions in patients. Physical and mental activity, enviormental factor s during early development and diatary restriction are causative and very promising approach for neuronal plasiticity. REFERENCES 1. Bertaux O., Toselli-Mollereau E., Auffray C., Devignes M., Alternative usage of 5 Vexons in the chicken nerve growth factor gene: refined characterization of a weakly expressed gene. Gene 2004, 334, 83-97. 2. Physiology of BDNF: focus on hypothalamic function Lucia Tapia-Arancibia,¤ Florence Rage, Laurent Givalois, and Sandor Arancibia Laboratoire de Plasticité Cérébrale, FRE 2693 CNRS, Université de Montpellier 2, Place Eugène Bataillon, 34095 Montpellier, Cedex 5, France Available online 18 May 2004 3. Kaplan DR, Miller FD., Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 2000, 10, 381-391. 4. 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