Text Box:  MainPage

Flowchart: Preparation: BDNF                 




Text Box: PESText Box: Drd4Text Box: alpha-MSH




Text Box: BDNFAutism


Bipolar Disorder


Text Box: TrkBText Box: Fyn

Text Box: Gsk3BText Box: NPY








Biochem Biophys Res Commun. 2007 Apr 27;356(1):200-6. Epub 2007 Mar 5.Click here to read Links

Genetic analyses of the brain-derived neurotrophic factor (BDNF) gene in autism.

Nishimura K, Nakamura K, Anitha A, Yamada K, Tsujii M, Iwayama Y, Hattori E, Toyota T, Takei N, Miyachi T, Iwata Y, Suzuki K, Matsuzaki H, Kawai M, Sekine Y, Tsuchiya K, Sugihara G, Suda S, Ouchi Y, Sugiyama T, Yoshikawa T, Mori N.

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Autism is a severe neurodevelopmental disorder defined by social and communication deficits and ritualistic-repetitive behaviors that are detectable in early childhood. Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of autism. In this study, we examined the SNP- and haplotypic-association of BDNF with autism in a trios-based association study (the Autism Genetic Resource Exchange). We also examined the expression of BDNF mRNA in the peripheral blood lymphocytes of drug-naïve autism patients and control subjects. In the TDT of autism trios, the SNP haplotype combinations showed significant associations in the autism group. BDNF expression in the drug-naïve 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.

PMID: 17349978 [PubMed - indexed for MEDLINE]


Behav Genet. 2007 May;37(3):487-97. Epub 2007 Jan 10.Click here to read Links

A study of how socioeconomic status moderates the relationship between SNPs encompassing BDNF and ADHD symptom counts in ADHD families.

Lasky-Su J, Faraone SV, Lange C, Tsuang MT, Doyle AE, Smoller JW, Laird NM, Biederman J.

Medical Genetics Research Program, Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.

Recent animal research suggests that brain-derived neurotrophic factor (BDNF), may mediate response to different environmental stimuli. In this paper, we evaluated the possible role of BDNF as a moderator of attention deficit hyperactivity disorder (ADHD) in the context of different socioeconomic classes. We genotyped ten single nucleotide polymorphisms (SNPs) in and around BDNF in 229 families and evaluate whether there are SNP-by-socioeconomic status (SES) interactions for attention deficit hyperactivity. We developed three quantitative phenotypes for ADHD from nine inattentive and nine hyperactive-impulsive symptoms that were used in SNP-by-SES interaction analyses using a new methodology implemented in the computer program PBAT. Findings were adjusted for multiple comparisons using the false discovery rate. We found multiple significant SNP-by-SES interactions using the inattentive symptom count. This study suggests that different SES classes may modify the effect of the functional variant(s) in and around BDNF to have an impact on the number of ADHD symptom counts that are observed. The two exons within BDNF represent potential functional variants that may be causing the observed associations.

PMID: 17216343 [PubMed - indexed for MEDLINE]

Neurosci Lett. 2007 Jun 8;420(1):45-48. Epub 2007 Apr 4.Click here to read Links

Serum levels of brain-derived neurotrophic factor in patients with schizophrenia and bipolar disorder.

Gama CS, Andreazza AC, Kunz M, Berk M, Belmonte-de-Abreu PS, Kapczinski F.

Laboratório de Psiquiatria Molecular, Centro de Pesquisas, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, 90035 003, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina: Psiquiatria, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400 – 2° andar, 90035 003, Porto Alegre, RS, Brazil; Schizophrenia Program, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, 90035 003, Porto Alegre, RS, Brazil.

There is evidence that major psychiatric discords such as schizophrenia (SZ) and bipolar disorder (BD) are associated with dysregulation of synaptic plasticity with downstream alterations of neurotrophins. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and performs many biological functions such as promoting the survival, differentiation, and plasticity of neurons. Variants in the BDNF gene increase the risk of SZ and bipolar disorder. Chronic administration of drugs used to treat SZ and BD, such as lithium, valproate, quetiapine, clozapine, and olanzapine, increases BDNF expression in rat brain. To examine serum BDNF, three groups of chronically medicated DSM-IV SZ patients, on treatment with clozapine (n=27), typical (n=14), and other atypical antipsychotics (n=19), 30 euthymic BD patients, and 26 healthy control had 5ml blood samples collected by venipuncture. Serum BDNF levels were significantly higher in SZ patients (p<0.001) when compared to either controls or euthymic BD patients. Increased BDNF in SZ patients might be related to the course of illness or to treatment variables. Prospective studies are warranted.

PMID: 17442489 [PubMed - as supplied by publisher]

J Neurosci. 2007 Oct 24;27(43):11533-42.Click here to read Links

Regulation of Na(V)1.2 channels by brain-derived neurotrophic factor, TrkB, and associated Fyn kinase.

Ahn M, Beacham D, Westenbroek RE, Scheuer T, Catterall WA.

Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.

Voltage-gated sodium channels are responsible for action potential initiation and propagation in neurons, and modulation of their function has an important impact on neuronal excitability. Sodium channels are regulated by a Src-family tyrosine kinase pathway, and this modulation can be reversed by specifically bound receptor phosphoprotein tyrosine phosphatase-beta. However, the specific tyrosine kinase and signaling pathway are unknown. We found that the sodium channels in rat brain interact with Fyn, one of four Src-family tyrosine kinases expressed in the brain. Na(V)1.2 channels and Fyn are localized together in the axons of cultured hippocampal neurons, the mossy fibers of the hippocampus, and cell bodies, dendrites, and axons of neurons in many other brain areas, and they coimmunoprecipitate with Fyn from cotransfected tsA-201 cells. Coexpression of Fyn with Na(V)1.2 channels decreases sodium currents by increasing the rate of inactivation and causing a negative shift in the voltage dependence of inactivation. Reconstitution of a signaling pathway from brain-derived neurotrophic factor (BDNF) to sodium channels via the tyrosine receptor kinase B (TrkB)/p75 neurotrophin receptor and Fyn kinase in transfected cells resulted in an increased rate of inactivation of sodium channels and a negative shift in the voltage dependence of inactivation after treatment with BDNF. These results indicate that Fyn kinase is associated with sodium channels in brain neurons and can modulate Na(V)1.2 channels by tyrosine phosphorylation after activation of TrkB/p75 signaling by BDNF.

PMID: 17959796 [PubMed - in process]

J Mol Neurosci. 2007;33(3):239-51. Epub 2007 Apr 17. Links

alpha-MSH Rescues Neurons from Excitotoxic Cell Death.

Forslin Aronsson A, Spulber S, Oprica M, Winblad B, Post C, Schultzberg M.

Division of Neurodegeneration and Neuroinflammation, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, SE-141 86, Stockholm, Sweden, Stefan.Spulber@ki.se.

This study investigates the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), on neurodegeneration, gliosis and changes in the neurotrophic protein brain-derived neurotrophic factor (BDNF) and in pro-inflammatory cytokines, following kainic acid (KA)-induced excitotoxic damage in the rat. Male Sprague-Dawley rats were treated with alpha-MSH (intraperitoneally, i.p.) at 20 min, and 24 and 48 h following administration of 10 mg/kg KA (i.p.). The animals were sacrificed at 30 min, 4 h, 24 h and 72 h after KA-administration and the levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were analysed in samples of hippocampus and hypothalamus. Levels of BDNF were analysed in the hippocampus. Stereological quantification showed a markedly reduced number of viable neurons in the CA1 pyramidal cell layer upon KA-administration as compared to animals injected with vehicle (p < 0.05, 79,587 +/- 25,554 vs. 145,254 +/- 27,871). The number of viable neurons upon administration of alpha-MSH was significantly higher than upon KA alone (p < 0.05, 119,776 +/- 33,158, KA+alpha-MSH vs. 79,587 +/- 27,554, KA + Saline). Astrocyte activation due to the KA-induced excitotoxicity was reduced, and the KA-induced increase in IL-1beta levels was delayed by the treatment with alpha-MSH. In conclusion, the degree of reduction in cell viability in the hippocampus CA1 pyramidal cell layer upon KA-induced excitotoxicity was similar to that seen previously upon global cerebral ischaemia. Furthermore, the administration of alpha-MSH resulted in a similar increase in cell viability, supporting the hypothesis that administration of alpha-MSH has rescuing effects on neurons subjected to excitotoxic insults.

PMID: 17952633 [PubMed - in process]

Brain Res. 2007 Sep 20; [Epub ahead of print]Click here to read Links

Peripheral electrical stimulation reversed the cell size reduction and increased BDNF level in the ventral tegmental area in chronic morphine-treated rats.

Chu NN, Zuo YF, Meng L, Lee DY, Han JS, Cui CL.

Neuroscience Research Institute, The Ministry of Education and Ministry of Public Health, Peking University, Beijing 100083, PR China; Department of Neurobiology, The Ministry of Education and Ministry of Public Health, Peking University, Beijing 100083, PR China; Key Laboratory of Neuroscience, The Ministry of Education and Ministry of Public Health, Peking University, Beijing 100083, PR China.

Chronic morphine administration induces functional and morphological alterations in the mesolimbic dopamine system (MLDS), which is believed to be the neurobiological substrate of opiate addiction. Our previous studies have demonstrated that peripheral electrical stimulation (PES) can suppress morphine withdrawal syndrome and morphine-induced conditioned place preference (CPP) in rats. The present study was designed to investigate if PES could reverse the cell size reduction induced by chronic morphine treatment in the ventral tegmental area (VTA), which is an important area of the MLDS. Immunohistochemical observations showed that the cell size of dopaminergic neurons in the VTA reduced significantly in the chronic morphine-treated rats with a concomitant decrease in the number of BDNF-positive cells compared to the saline-treated rats. A much milder morphological change, accompanying with an increased number of BDNF-positive cells, was observed in dopaminergic neurons in the rats that received repeated 100 Hz PES after morphine withdrawal. In another experiment, enzyme-linked immunosorbent assay (ELISA) reconfirmed a significant up-regulation of BDNF protein level in the VTA in the rats received 100 Hz PES after morphine abstinence. These results indicate that PES could facilitate the morphological recovery of the VTA dopaminergic cells damaged by chronic morphine treatment and up-regulate the BDNF protein level in the VTA. Activation of endogenous BDNF by PES may play a role in the recovery of the injured dopaminergic neurons in the morphine addictive rats.

PMID: 17945205 [PubMed - as supplied by publisher]




















Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reduces energy intake.

Wang C, Bomberg E, Billington C, Levine A, Kotz CM.

Veterans Affairs Medical Center, Research Service (151), One Veterans Drive, Minneapolis, MN 55417, USA. cwang@umn.edu

Recent studies show that brain-derived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor tyrosine kinase B (TrkB) are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF in the hypothalamic paraventricular nucleus (PVN) on feeding. BDNF injected unilaterally or bilaterally into the PVN of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0- to 24-h and 24- to 48-h postinjection intervals. Effective doses producing inhibition of feeding behavior did not establish a conditioned taste aversion. PVN BDNF significantly decreased PVN neuropeptide Y (NPY)-induced feeding at 1, 2, and 4 h following injection. BDNF administration in the PVN abolished food-restriction-induced NPY gene expression in the hypothalamic arcuate nucleus. In conclusion, BDNF in the PVN significantly decreases food intake and body weight gain, suggesting that the PVN is an important site of action for BDNF in its effects on energy metabolism. Furthermore, BDNF appears to interact with NPY in its anorectic actions, although a direct effect on NPY remains to be established.

PMID: 17581841 [PubMed - in process]]

Mol Psychiatry. 2005 Oct;10(10):939-43.Click here to read  Links

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD.


Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, Raybould R, Langley K, Bray N, Fitzgerald M, Owen MJ, O'Donovan MC, Gill M, Thapar A, Craddock N.

Developmental Psychiatry, University of Cambridge, Cambridge, UK. lk255@cam.ac.uk

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR=1.6, P=0.02) with a strong paternal effect (paternal transmissions: OR=3.2, P=0.0005; maternal transmissions: OR=1.00; P=1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved.

PMID: 15940292 [PubMed - indexed for MEDLINE

Dev Biol. 2003 Nov 15;263(2):216-30.Click here to read Links

Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons.

Jourdi H, Iwakura Y, Narisawa-Saito M, Ibaraki K, Xiong H, Watanabe M, Hayashi Y, Takei N, Nawa H.

Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.

Postsynaptic molecules with PDZ domains (PDZ proteins) interact with various glutamate receptors and regulate their subcellular trafficking and stability. In rat neocortical development, the protein expression of AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic factor (BDNF), appeared to contribute to this process, regulating the PDZ protein expression. In neocortical cultures, BDNF treatment upregulated SAP97, GRIP1, and Pick1 PDZ proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The BDNF-triggered increases in PDZ proteins resulted in the elevation of their total association with the AMPA receptors GluR1 and GluR2/3, which led to the increase in AMPA receptor proteins. When Sindbis viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1 and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the BDNF-triggered GluR1 increase. In agreement, coexpression of SAP97 and GluR1 in nonneuronal HEK293 cells increased both proteins compared with their single transfection, implying mutual stabilization. This work reveals a novel function of BDNF in postsynaptic development by regulating the PDZ protein expression.

PMID: 14597197 [PubMed - indexed for MEDLINE]

Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children.

Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J.

Child and Adolescent Research and Education Program, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06511, USA. joan.kaufman@yale.edu

BACKGROUND: Child abuse and genotype interact to contribute to risk for depression in children. This study examined gene-by-gene and gene-by-environment interactions. METHODS: The study included 196 children: 109 maltreated and 87 nonmaltreated comparison subjects. Measures of psychiatric symptomatology and social supports were obtained using standard research instruments, and serotonin transporter (5-HTTLPR) (locus SLC6A4) and brain-derived neurotrophic factor (BDNF) (variant val66met) genotypes were obtained from saliva-derived DNA specimens. Population structure was controlled by means of ancestral proportion scores computed based on genotypes of ancestry informative markers in the entire sample. RESULTS: There was a significant three-way interaction between BDNF genotype, 5-HTTLPR, and maltreatment history in predicting depression. Children with the met allele of the BDNF gene and two short alleles of 5-HTTLPR had the highest depression scores, but the vulnerability associated with these two genotypes was only evident in the maltreated children. A significant four-way interaction also emerged, with social supports found to further moderate risk for depression. CONCLUSIONS: To the best of our knowledge, this is the first investigation to demonstrate a gene-by-gene interaction conveying vulnerability to depression. The current data also show a protective effect of social supports in ameliorating genetic and environmental risk for psychopathology.

PMID: 16458264 [PubMed - indexed for MEDLINE]