Brain derived neurotrophic factor-BDNF- and Autism-I
A very graphic and simple presentation of the function (please see figure in color)
BDNF binds at least two receptors on the cells
1-TRkB (pronounced TRACK B). This is a receptor tyrosine kinase. Kinase is a kind of enzyme that transfers phosphate groups (PO4 with 3 negative charges) from ATP (Adenosin TriPhosphate) to substrates. This is named phosphorylation. The tyrosine kinase (TK) adds phosphate to a tyrosine of an enzyme.
And here a simple explanation of what is the function and how the process is in terms of how TK begins a cascade of signals
You can find here
some images on neurotrophins- and this is the only reason I posted-nothing to do with promotion of nothing, but the demonstration of the status of the science in terms of testing
2- LN GFR or low affinity nerve growth factor receptor, also known as p75-NTR, whose role is less clear. It seems a sink for neurofactors. This factor can signal a cell to die by apoptosis. The p75NTR belongs to the tumor necrosis factor (TNF) receptor family and was the first identified neurotrophin receptor
Low levels of BDNF have been linked to depression, OCD, Alzheimer, Rett, Huntigton and dementia. BDNF modulates excitatory and inhibitory synaptic transmission by inhibition of GABA (gama amino butyric acid)-A receptors.
Here you can find more information on neurotrophic factors- if you want.
You can find in figure 2 that NGF activates TrkA receptor, BDNF activates TrkB receptors such as NT4/5 and NT-3 activates TrkC, all the Trk are tyrosine kinase receptors.
The Trk-independent pathway of p75NTR increases intracellular ceramide levels and further activates Nuclear Factor k B (NFkB) transcription factor and Jun N- terminal K kinase.
BDNF is a neurotrophin, such as Nerve growth factor or NGF, neurotrophin 3- NT3 and neurotrophin 4/-NT4/5. There are also neuropoietins, Insulin-like Growth Factors 1 and 2, transforming growth factors, fibroblast growth factors and finally other factors.
There is a theory, the Target Field theory. In this theory the axons of neurons growth towards the higher concentration of tropic factors in the target tissue. Neurons that succeed are maintained; if they do not succeed they die. In is interesting that they act like dimmers and they all share six cysteine residues (an aminoacid with SH bond).
From here thereafter, I will link a certain study, will transcribe some interesting conclusion from the authors in italics and I will add my own ideas about in normal.
Studies on knockout mice on neurotrophin have been unsuccessful because it is considered that probably a system of compensation is acting in the CNS in the development, a back up system that allows the differentiation of the neurotrophins to compensate for the loss of some. Even more , the knockout mice lacks the gene; probably this situation is totally different to a decrease/increase of the amount of a neurotrophin ( or its receptor) in cells.
As you know, neurexin/neuroligin have been very much mentioned about autism lately.
From Columbia Health Sciences
Here there is an explanation of what the neuroligin/neuroxin couple do in terms of concerted mechanism of synaptogenesis.
Development and Regulation of Dendritic Spine Synapses
Let´s go to focus on neurotrophin and neuroligin/neurexin. Please go to the figure 1. The “Connections” between the dendritic spine and the presynaptic terminal are N cadherin with B catenin in blue; neuroligin and neurexin in light brown and ephrin with EphR.
From here, not only neurotrophin but also neuroligin/neurexin are extremely important to generate dendritic spine synapses. It seems that neuroligin/neurexin are active mainly in the first step of synapse formation
What is the role of a neurotrophic factor?
In figure 1 you can find a map of the cascade of reactions that the BDNF tyrosine kinase domain produces.
Basically the tyrosin kinase receptor or TrkB- through the BDNF- activates
A-the phospholipase C pathway (PLC), that produces Ca and diacylglicerol and affects the protein kinase C (PKC) and CAM (Ca+2/calmodulindependent protein kinase) kinases
B-the phosphatidylinositol 3-OH (PI-3-K)- PI-3-K activates AKT ( a serine/threonine kinase or Protein Kinase B) and p-70 s6 that act on Caspaces and Bad proteins (proapoptotic therefore these are signals to the cell to die). The PI3K dependent AKT activation could be regulated through the PTEN (remember the last news about a role in autism), which work as the opposite of PI3K. AKT regulates the cellular survival by binding and regulating several receptors, such as nuclear factor kB or NFkB.
About PTEN, the link has been considered to neurodegenerative disease, not autism per se.
c-The RAS (a protein G that switches in activated and deactivated forms RAS GDP and RAS GTP; the diference is from di (D) to tri (T) Phosphate) activation the change is related to one group phosphate more added. RAS activates a number of pathways but an especially important one seems to be, the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins. MAP is a Serine/threonine-specific protein kinase that respond to extracellular stimuli (mitogens). MAP regulates mitosis differentiation and apoptosis of cells.
To date, four distinct groups of MAPKs have been characterized in mammals:
I-extracellular signal-regulated kinases (ERKs). The ERKs (also known as classical MAP kinases) signaling pathway is preferentially activated in response to growth factors and a tumor promoter, and regulates cell proliferation and cell differentiation.
II-Jun N-terminal kinases (JNKs), also known as stress-activated protein kinases (SAPKs).
III-p38 isoforms. Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis.
IV-ERK5. ERK5, which has been found recently, is activated both by growth factors and by stress stimuli, and it participates in cell proliferation.
Yes, it is extremely difficult. To have a picture of how difficult, I have found these very illustrative:
4-Protein Kinase C-PKC
6-Protein Kinase B or AKT
Please localize the PTEN, to the left.
I am very enthusiastic on all this but I have also a headache if I try to understand everything. I have found useful to use these graphs to follow the explanation of the manuscripts, that are per se very complicated.Indeed. Please do not look for the commercial aspect- the pathways have been posted by a company of testing-, I considered the pathways clear- and colourful. I think is a good picture of the complexity we are talking about, don´t you think?
About BDNF roles
1-Exposure to stress and corticoesterone has been shown to decrease the expression of BDNF in rats and lead to eventual atrophy of hippocampus
2-Glutamate, voluntary exercise, caloric restriction, intellectual stimulation increase expression of BDNF.
3-Targeted disruption of the BDNF gene pertubs brain and sensory neuron development, but not motor neuron development.
Each kind of neurotrophin could be linked to an specific disease or susceptibility.
Neurotrophin can also play a role in immune modulation.
4- Brain-Derived Neurotrophic Factor Stimulates Energy Metabolism in Developing Cortical Neurons
Some comments particularly interesting
“The increased Na+-dependent amino acid uptake by BDNF is followed by an enhancement of overall protein synthesis associated with the differentiation of cortical neurons. Together, these data demonstrate the ability of BDNF to stimulate glucose utilization in response to an enhanced energy demand resulting from increases in amino acid uptake and protein synthesis associated with the promotion of neuronal differentiation by BDNF. Results revealed that BDNF increases glucose utilization and the expression of the neuronal glucose transporter GLUT3.
Thus BDNF knock-out mice exhibit substantially reduced numbers of cranial and spinal sensory neurons as well as marked decreases in the expression of neuropeptide Y (NPY) and calcium-binding proteins in specific brain regions, including cerebral cortex and hippocampus. It is also well established that BDNF increases peptidergic differentiation of GABA-containing neurons as it stimulates the expression of specific neuropeptides such as somatostatin, substance P, NPY, and cholecystokinin both in vitro and in vivo In the CNS BDNF promotes structural changes in axonal and dendritic arborisation.Thus BDNF increases the length and complexity of dendrites of cortical pyramidal neurons.
Our in vitro observations provide evidence that BDNF plays a determinant role as a stimulator of glucose utilization and GLUT3 expression in response to the increased energy demand resulting from the enhanced amino acid uptake and protein synthesis associated with the promotion of neuronal development by this neurotrophic factor”
And I thought in Ian´s post (from A shade of Grey) on increased demands of nutrients and minicolumns posts ; if there is a higher brain growth the first 2 years of life when I read this. Also in the transport system of aminoacids, carboxylic acids and glucose through the BBB in children.
5- BDNF part of a serie of genes involved in ASD?
It is important to remember that c- MET gene polymorphisms has been reported in families with MORE than one child with autism. cMET is also a receptor tyrosine kinase.
I only want to mention
How c-met ( in magenta) is related to our PI3K ( in red) activated by BDNF. cMET affects PI3K and AKT.
How can we think that only one or two genes can affect the overall function of for example this pathway? How someone on the earth can present something for sure with the level of complexity that this has is something out of my understanding (what about interactions between genes?)
I want to focus on BDNF and autism
About role and function of BDNF
The main conclusions from this manuscript
a-There are several theories about the neuronal release of neurotrophins.. They seem contradictory depending of the kind of neuron used (cortical or from the hippocampus)
b-NT-3 and BDNF- but not NGF-modulate the efficiency of synaptic transmission.
c-Neurotrophins induce the presynaptic release of glutamate(excitatory), GABA (inhibitory), and acethylcholine.
d-There are clues about the direct interaction of BDNF/TRkB with synapsin, a protein required for the release of vesicles.
e-Neurotrophins mediates the activation of ion channels (Na+, Ca+2) and interact with NMDA-N methyl D aspartate- receptors.
f-Neurotrophins participate in neuronal plasticity.BDNF is directly involved in hippocampal Long Term Potentiation or LPT ( involved in learning and memory).
g-The interplay between slow and fast events must be considered. The key question is how spatial and temporal availability of acutely secreted neurotrophins contribute to multiple pathways that regulate neuronal function in the CNS:
How Visual Stimulation Turns Up Bdnf Genes to Shape the Brain
"This suggests that sensory experience regulates different genes in your brain depending on your age and past experience. Thus, nurture, our experience of the world via our senses, acts through nature, sets of genes, to alter brain circuits."
The sensory integration and how the sensorial information is analyzed impact the neurotrophins and modulates their activity.
BDNF and Huntigton´s disease
Huntingtin protein is the transcription factor that allows the expression of BDNF.In Huntigton´s BDNF is very low.
Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism.
“BDNF expression in the drug-naive autistic group was found to be significantly higher than in the control group. We suggest that BDNF has a possible role in the pathogenesis of autism through its neurotrophic effects on the serotonergic system”
It is clear that autism is well different than Huntigton´s disease from the BDNF point of view. BDNF is overexpressed in autism, not underexpressed. BDNF is higher in autism.
Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau-Kleffner syndrome, and epilepsy.
“BDNF levels and IgG/IgM autoantibodies to BDNF, ECs, MBP, and histones were measured in children with autism, childhood disintegrative disorder (CDD), pervasive developmental delay-not otherwise specified (PDD-nos), acquired epilepsy, Landau-Kleffner syndrome (LKS); healthy children (HC), and children with non-neurological illnesses (NNI).
Children with developmental disorders and epilepsy have higher autoantibodes (AAs) to several neural antigens compared to controls. The presence of both BDNF AAs and elevated BDNF levels in some children with autism and CDD suggests a previously unrecognized interaction between the immune system and BDNF.”
Impaired cerebellar development and function in mice lacking CAPS2, a protein involved in neurotrophin release.
CAPS2 mediated BDNF release may be involved in synaptic plasticity even in the fully developed cerebellar circuit, because BDNF is regulatory of Purkinje cells synapses. CAPS2 is specifically associated with the cerebellar postnatal development during which tens of millions of neurons undergo vigorous differentiation events.
Therefore we have autoantibodies to BDNF, high levels of BDNF in autism and the reported impact of BDNF in cerebellar postnatal development, mainly Purkinje cells synapsis.
High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression.
“Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state”
There are beta amyloid precursor protein and BDNF high levels in autism.
Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism.
Now, it seems that at birth BDNF is overexpressed and in adult autistic male is lower than controls.
a-Is this a common finding in non-autistic with development or this is an isolated case?
b-Why/how/when BDNF changes with age?
Neurotrophic factors in the pathogenesis of Rett syndrome.
“Impairment in dendritic development in Rett syndrome could be the consequence of cholinergic deficiency and of neurotrophic factor/glutamate imbalance. Cholinergic gene expression might be influenced by the Rett syndrome gene directly or via the neurotrophic factor system.”
The implicancies of impact in cholinergic, glutamate systems are clear from this report.
Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation
"Neonatal concentrations of VIP (vasoactive intestinal peptide), CGRP (calcitonin gene-related peptide) , BDNF, and NT4/5 (neurotrophin 4/5) 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"
Localization of neurotrophins and their high-affinity receptors during human enteric nervous system development.
From infancy through adulthood, TrkA and TrkB immunoreactivities were localized to both enteric ganglion cells and glia, whereas TrkC was localized exclusively to enteric ganglion cells. In postnatal intestine, BDNF immunoreactivity was primarily localized to enteric ganglion cells, with NT-3 localized to enteric plexuses, intermuscular basal lamina, and along or between circular and longitudinal smooth muscle cells. CONCLUSIONS: These data indicate that neurotrophic influences may be involved in ENS development and survival, with potential importance in functional differentiation disorders of the intestinal ENS.
Nutr Rev. 2006 Sep;64(9):428-32. Links
Regulation of the NMDA receptor: implications for neuropsychological development.Levenson CW.
Recent work has shown that zinc is involved in the developmental regulation of neurotrophins and N-methyl-D-aspartate (NMDA) receptors, controlling use of glutamate as a neurotransmitter in the central nervous system (CNS). This is particularly important in the hippocampus, a region of the brain involved in learning and memory, and is an intriguing link to the role of zinc in neuropsychological development.
It is supposed that this is kind of a feedback.
NMDA receptor stimulation induces the influx of extracelular Ca+2 that may evoke the release of BDNF and the activation of TRkB. TrkA is the receptor of NGF and TrkB is the receptor of BDNF. Interferon gamma increased NFG expression, down regulate BDNF expression The chronic blocking of NMDA receptors has a secondary effect the inhibition of BDNF synthesis in the hippocampus and may impair neuronal development. Brain specific phosphorylation of MECP2 regulates BDNF transcription, dendritic growth and spine maturity
Critical Periods of Vulnerability for the Developing Nervous System: Evidence from Humans and Animal Models
In addition, a number of environmental chemicals and pharmaceutical agents alter the expression and/or signal transduction of these trophic molecules, including ethanol (146-152), methyl mercury (153,154), aluminum (155), and cholinesterase inhibitors (138,139,156). Although neurotrophic factors are perturbed in experimental animals after exposure to environmental agents, the involvement of these factors in developmental disorders has only recently been suggested in humans (157).
Dietary restriction (DR) increases the lifespan of rodents and increases their resistance to several different age-related diseases including cancer and diabetes. Beneficial effects of DR on brain plasticity and neuronal vulnerability to injury have recently been reported, but the underlying mechanisms are unknown. We report that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex, and striatum of rats maintained on a DR regimen compared to animals fed ad libitum (AL). Seizure-induced damage to hippocampal neurons was significantly reduced in rats maintained on DR, and this beneficial effect was attenuated by intraventricular administration of a BDNF-blocking antibody. These findings provide the first evidence that diet can effect expression of a neurotrophic factor, demonstrate that BDNF signaling plays a central role in the neuroprotective effect of DR, and proffer DR as an approach for reducing neuronal damage in neurodegenerative disorders.
Well. The effect/nature/role of BDNF and its importance from here is clear. Now, how can the environment modulate this neurotrophin and the signals of TrkB? There are a lot of reported clues about. I will let the analysis of them for a forthcoming post.
From Dr Julie Grether Epidemiology of Autism: Current Controversies and Research Directions “We don’t yet know if BDNF and other identified neurotrophins and neuropeptides actually contribute to the pathogenesis of autism or may only represent markers of the disorder. Available evidence regarding their role in early brain development and abnormal levels present in newborns, if confirmed, strongly suggest, however, that these proteins may have etiologic significance”.
The other side of BDNF
a-Neurotrophin-mediated potentiation of neuronal injury.
a more specific manuscript
The p75 receptor is related to the Janus K Pathway and these are signals to the cells to die. It seems that VIP (vasoactive intestinal peptide) can prevent partially neuronal death. It seems that, depending on conditions, BDNF can be toxic to cortical grey matter. An enzyme NADPH oxidase seems to be involved,
b-The role of NADPH oxidase, neuronal nitric oxide synthase and poly(ADP ribose) polymerase in oxidative neuronal death induced in cortical cultures by brain-derived neurotrophic factor and neurotrophin-4/5.
Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation.
“We found that three distinct mechanisms contribute to neuronal injury by generating ROS and oxidative stress, each operating at a different stage of ischemia and reperfusion. In response to hypoxia, mitochondria generate an initial burst of ROS, which is curtailed once mitochondria depolarize or prevented by previous depolarization with uncoupler. A second phase of ROS generation that followed after a delay was blocked by the xanthine oxidase (XO) inhibitor oxypurinol. This phase correlated with a rise in [Mg2+]c, suggesting XO activation by accumulating products of ATP consumption. A third phase of ROS generation appeared at reoxygenation. This was blocked by NADPH oxidase inhibitors and was absent in cells from gp91(phox-/-) knock-out mice. It was Ca2+ dependent, suggesting activation by increased [Ca2+]c during anoxia, itself partly attributable to glutamate release. Inhibition of either the NADPH oxidase or XO was significantly neuroprotective. Thus, oxidative stress contributes to cell death over and above the injury attributable to energy deprivation”
Potentiated necrosis of cultured cortical neurons by neurotrophins
Characterization of the toxic mechanism triggered by Alzheimer's amyloid-beta peptides via p75 neurotrophin receptor in neuronal hybrid cells.
Remember please the high levels of beta amyloid protein found in some autistics.
Considering these reports, BDNF can activate the p75 receptor and include the activation of NADPH oxidase, pro stress oxidative.
What is the balance between the pro-oxidative stress vs the protective effect when BDNF levels are high, such as in autism?
Gene-Gene interactions, polygenia and epigenetics
Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders.
“When diseases or disorders or traits are due to genetic factors, there are several mechanisms by which they can inherited. Such conditions can essentially be divided into single gene disorders and polygenic disorders. Single gene disorders include hemophilia, cystic fibrosis, neurofibromatosis and Huntington disease. In single gene disorders a rare mutation results in the complete disruption of the function of a gene. Some of the greatest advances in genetics during the past 100 years have come from the elucidation of the genes for virtually every single gene disorder. Their DNA has been cloned, sequenced and the gene localized to a specific chromosomal region.
Polygenic disorders, by contrast, are due to the interactive or epistatic effects of many different genes on different chromosomes, each gene contributing to only a small part of the picture (variance). These genes interact with environmental factors. Except for a few rare families , all behavioral disorders such as manic-depressive disorder, schizophrenia, major depression, panic disorder, autism and ADHD  are likely to be polygenic. While we do not yet know the total number of genes involved, it is likely to range from 50 to several hundred. In contrast to the gene defects for single gene disorders (mutations), the defects for polygenic disorders are much less severe, otherwise they would be single gene disorders. Thus, we call them gene variants instead of gene mutations, and individuals have to inherit a number of them if they are to cause a clinical effect . A second distinction is that mutations that severely affect gene function are very rare. Since they are often present in less than 1 in 100,000 individuals the diseases they cause are also very rare. In fact, all single gene disorders combined affect less than 1.5% of the population. By contrast, the gene variants involved in polygenic disorders are common and polygenic disorders themselves are common. This "common gene, common disorder" theory of polygenic disorders has gained wide acceptance. An alternative theory, of "rare gene, common disorder," postulates a large number of rare mutations of different genes .In association studies of a wide range of behavioral disorders, even when the association is significant the percent of the variance attributable to that gene is usually in the 0.5 to 3% range and averages less than 1.5%. This suggests that even if genes only account for 72 to 95% of the total variance, 50 or more different genes would be involved […]. This does not mean that every affected individual has inherited 50 or more of these variants. It is likely that only a subset of the total potential set of gene variants is required in a given individual. Because of this, polygenic disorders show a great deal of genetic heterogeneity […]. That is, different individuals with ADHD are likely to have inherited somewhat different sets of genes. However, each affected ADHD individual must have inherited enough gene variants to pass a liability threshold, allowing them to develop ADHD.
Now, more and more I think on autism as a polygenic disorder.
The Genetics of Autism
Some of the genes that have been reported to be linked or associated to autism are:
1-Chromatin remodelling and gene expression:MeCp2 (importance in Rett syndrome); FMRP (important in fragile X mental retardation),EN2, HOXA2 and WNT (the last three transcription factors dysregulated).
2-Actin cytoskeleton dynamics- look please for the MET pathway and you will find the actin to the left.TSC1/TSC2 (important in tuberous sclerosis) ; NF1 ( important in neurofibromatosis);cAMPGEF. These produce inactivation of GTPase (inactivation of an enzyme).
3-Synaptic scaffolding proteins: Schank Dendrite induction, binding partner of neuroligin
4-Receptors and transporters.GRIN2A (A NMDA receptor subunit), GriK2 (kainite receptor subunit), GABAr (GABA receptor), SLOSA4 (serotonine trasnporter¡), SLC 25 A (aspartate-glutamate); OXTR (oxytocin receptor) and AVPR1 (vasopressin receptor). 5 HTT is the serotonin transporter.
5-Second messenger problems:PRKCB1 (protein kinase C); CaCNA (Ca+2 Channel), NBEA (PKA(Protein Kinase A) anchor protein.
6-Cell adhesión molecules NLGN-3; NLGN-4 (NLGN seems important in autism) ; NrCAM
7-Secreted proteins: RELN, LAMB (laminin).
If you can get the manuscript
Searching for way outs of the autism maze:…” from Persico and Burgeroun from Trends in Neuroscience please go to the figure 1 and you will have a graph in colors about the proteins that can be altered in autism related to synapsis.
BDNF would be related to second messenger problems and cell adhesion molecules because of the signals that these receptors produce.
Some clues of correlations
1-Wang H, Chan SA, Ogier M, Hellard D, Wang Q, Smith C, Katz DM. Related Articles,Dysregulation of brain-derived neurotrophic factor expression and neurosecretory function in Mecp2 null mice.J Neurosci. 2006 Oct 18;26(42):10911-5.
2- Neurobiol Dis. 2002 Oct;11(1):221-9.BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampus.Castren M, Lampinen KE, Miettinen R, Koponen E, Sipola I, Bakker CE, Oostra BA, Castren E.
3-BDNF induced the phosphorylation of tuberin / There are results that are consistent with a model wherein neurofibromin acts as a negative regulator of neurotrophin-mediated signaling for survival of embryonic peripheral neurons.
4-Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS, Backos DS, Carvalho AL, Esteban JA, Duarte CB.BDNF regulates the expression and the synaptic delivery of AMPA receptor subunits in hippocampal neurons.J Biol Chem. 2007 Mar 2;
5-Chen Q, He S, Hu XL, Yu J, Zhou Y, Zheng J, Zhang S, Zhang C, Duan WH, Xiong ZQ.Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent brain-derived neurotrophic factor gene regulation and limbic epileptogenesis.J Neurosci. 2007 Jan 17;27(3):542-52.
6-Carrasco MA, Castro P, Sepulveda FJ, Tapia JC, Gatica K, Davis MI, Aguayo LG.
Regulation of glycinergic and GABAergic synaptogenesis by brain-derived neurotrophic factor in developing spinal neurons.Neuroscience. 2007 Mar 16;145(2):484-94. Epub 2007 Feb 15.
7-Neurotrophins modulate neuron-glia interactions at a vertebrate synapse.
“Our results indicate that acute application of both NT-3 and BDNF, but not NGF, increased PSC (perisynaptic Schwann cells) Ca2+ responses. BDNF increased PSC responsiveness through potentiation of ATP (adenosine triphosphate) responses while NT-3 modulated muscarinic acetylcholine receptor signalling.”
8-Taniguchi N, Shinoda Y, Takei N, Nawa H, Ogura A, Tominaga-Yoshino K. Possible involvement of BDNF release in long-lasting synapse formation induced by repetitive PKA activation. Neurosci Lett. 2006 Oct 2;406(1-2):38-42. 2006 Aug 9.
With this very partial picture, it seems to me that the picture is extremely complex to discard nothing. With such a number of interactions, retrograde signals and feeback, multiple changes depending on the development. What if BDNF roles are very much wide and complete and interelated with other systems ( immune system, gastrointestinal system)?
What do you think?