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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.
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