Ser46 phosphorylation and prolyl-isomerase Pin1-mediated isomerization of p53 are key events in p53-dependent apoptosis induced by mutant huntingtin.

PubMed

Grison, Alice; Mantovani, Fiamma; Comel, Anna; Agostoni, Elena; Gustincich, Stefano; Persichetti, Francesca; Del Sal, Giannino

2011-11-01

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for huntingtin protein. Several mechanisms have been proposed by which mutant huntingtin (mHtt) may trigger striatal neurodegeneration, including mitochondrial dysfunction, oxidative stress, and apoptosis. Furthermore, mHtt induces DNA damage and activates a stress response. In this context, p53 plays a crucial role in mediating mHtt toxic effects. Here we have dissected the pathway of p53 activation by mHtt in human neuronal cells and in HD mice, with the aim of highlighting critical nodes that may be pharmacologically manipulated for therapeutic intervention. We demonstrate that expression of mHtt causes increased phosphorylation of p53 on Ser46, leading to its interaction with phosphorylation-dependent prolyl isomerase Pin1 and consequent dissociation from the apoptosis inhibitor iASPP, thereby inducing the expression of apoptotic target genes. Inhibition of Ser46 phosphorylation by targeting homeodomain-interacting protein kinase 2 (HIPK2), PKCδ, or ataxia telangiectasia mutated kinase, as well as inhibition of the prolyl isomerase Pin1, prevents mHtt-dependent apoptosis of neuronal cells. These results provide a rationale for the use of small-molecule inhibitors of stress-responsive protein kinases and Pin1 as a potential therapeutic strategy for HD treatment.

Genomic Organization and Identification of Promoter Regions for the BDNF Gene in the Pond Turtle Trachemys scripta elegans

PubMed Central

Zheng, Zhaoqing; Keifer, Joyce

2014-01-01

Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal development and synaptic function. The BDNF gene undergoes significant activity-dependent regulation during learning. Here, we identified the BDNF promoter regions, transcription start sites, and potential regulatory sequences for BDNF exons I–III that may contribute to activity-dependent gene and protein expression in the pond turtle Trachemys scripta elegans (tBDNF). By using transfection of BDNF promoter/luciferase plasmid constructs into human neuroblastoma SHSY5Y cells and mouse embryonic fibroblast NIH3T3 cells, we identified the basal regulatory activity of promoter sequences located upstream of each tBDNF exon, designated as pBDNFI–III. Further, through chromatin immunoprecipitation (ChIP) assays, we detected CREB binding directly to exon I and exon III promoters, while BHLHB2, but not CREB, binds within the exon II promoter. Elucidation of the promoter regions and regulatory protein binding sites in the tBDNF gene is essential for understanding the regulatory mechanisms that control tBDNF gene expression. PMID:24443176

Genomic organization and identification of promoter regions for the BDNF gene in the pond turtle Trachemys scripta elegans.

PubMed

Ambigapathy, Ganesh; Zheng, Zhaoqing; Keifer, Joyce

2014-08-01

Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal development and synaptic function. The BDNF gene undergoes significant activity-dependent regulation during learning. Here, we identified the BDNF promoter regions, transcription start sites, and potential regulatory sequences for BDNF exons I-III that may contribute to activity-dependent gene and protein expression in the pond turtle Trachemys scripta elegans (tBDNF). By using transfection of BDNF promoter/luciferase plasmid constructs into human neuroblastoma SHSY5Y cells and mouse embryonic fibroblast NIH3T3 cells, we identified the basal regulatory activity of promoter sequences located upstream of each tBDNF exon, designated as pBDNFI-III. Further, through chromatin immunoprecipitation (ChIP) assays, we detected CREB binding directly to exon I and exon III promoters, while BHLHB2, but not CREB, binds within the exon II promoter. Elucidation of the promoter regions and regulatory protein binding sites in the tBDNF gene is essential for understanding the regulatory mechanisms that control tBDNF gene expression.

Methionine increases BDNF DNA methylation and improves memory in epilepsy.

PubMed

Parrish, R Ryley; Buckingham, Susan C; Mascia, Katherine L; Johnson, Jarvis J; Matyjasik, Michal M; Lockhart, Roxanne M; Lubin, Farah D

2015-04-01

Temporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus. Using the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model. We found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade. Our findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE.

Bifunctional Anti-Huntingtin Proteasome-Directed Intrabodies Mediate Efficient Degradation of Mutant Huntingtin Exon 1 Protein Fragments

PubMed Central

Butler, David C.; Messer, Anne

2011-01-01

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a trinucleotide (CAG)n repeat expansion in the coding sequence of the huntingtin gene, and an expanded polyglutamine (>37Q) tract in the protein. This results in misfolding and accumulation of huntingtin protein (htt), formation of neuronal intranuclear and cytoplasmic inclusions, and neuronal dysfunction/degeneration. Single-chain Fv antibodies (scFvs), expressed as intrabodies that bind htt and prevent aggregation, show promise as immunotherapeutics for HD. Intrastriatal delivery of anti-N-terminal htt scFv-C4 using an adeno-associated virus vector (AAV2/1) significantly reduces the size and number of aggregates in HDR6/1 transgenic mice; however, this protective effect diminishes with age and time after injection. We therefore explored enhancing intrabody efficacy via fusions to heterologous functional domains. Proteins containing a PEST motif are often targeted for proteasomal degradation and generally have a short half life. In ST14A cells, fusion of the C-terminal PEST region of mouse ornithine decarboxylase (mODC) to scFv-C4 reduces htt exon 1 protein fragments with 72 glutamine repeats (httex1-72Q) by ∼80–90% when compared to scFv-C4 alone. Proteasomal targeting was verified by either scrambling the mODC-PEST motif, or via proteasomal inhibition with epoxomicin. For these constructs, the proteasomal degradation of the scFv intrabody proteins themselves was reduced<25% by the addition of the mODC-PEST motif, with or without antigens. The remaining intrabody levels were amply sufficient to target N-terminal httex1-72Q protein fragment turnover. Critically, scFv-C4-PEST prevents aggregation and toxicity of httex1-72Q fragments at significantly lower doses than scFv-C4. Fusion of the mODC-PEST motif to intrabodies is a valuable general approach to specifically target toxic antigens to the proteasome for degradation. PMID:22216210

HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity

PubMed Central

Mattis, Virginia B.; Tom, Colton; Akimov, Sergey; Saeedian, Jasmine; Østergaard, Michael E.; Southwell, Amber L.; Doty, Crystal N.; Ornelas, Loren; Sahabian, Anais; Lenaeus, Lindsay; Mandefro, Berhan; Sareen, Dhruv; Arjomand, Jamshid; Hayden, Michael R.; Ross, Christopher A.; Svendsen, Clive N.

2015-01-01

Huntington's disease (HD) is a fatal neurodegenerative disease, caused by expansion of polyglutamine repeats in the Huntingtin gene, with longer expansions leading to earlier ages of onset. The HD iPSC Consortium has recently reported a new in vitro model of HD based on the generation of induced pluripotent stem cells (iPSCs) from HD patients and controls. The current study has furthered the disease in a dish model of HD by generating new non-integrating HD and control iPSC lines. Both HD and control iPSC lines can be efficiently differentiated into neurons/glia; however, the HD-derived cells maintained a significantly greater number of nestin-expressing neural progenitor cells compared with control cells. This cell population showed enhanced vulnerability to brain-derived neurotrophic factor (BDNF) withdrawal in the juvenile-onset HD (JHD) lines, which appeared to be CAG repeat-dependent and mediated by the loss of signaling from the TrkB receptor. It was postulated that this increased death following BDNF withdrawal may be due to glutamate toxicity, as the N-methyl-d-aspartate (NMDA) receptor subunit NR2B was up-regulated in the cultures. Indeed, blocking glutamate signaling, not just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death phenotype. This study suggests that the pathogenesis of JHD may involve in part a population of ‘persistent’ neural progenitors that are selectively vulnerable to BDNF withdrawal. Similar results were seen in adult hippocampal-derived neural progenitors isolated from the BACHD model mouse. Together, these results provide important insight into HD mechanisms at early developmental time points, which may suggest novel approaches to HD therapeutics. PMID:25740845

Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus.

PubMed

Coskunoglu, Aysun; Orenay-Boyacioglu, Seda; Deveci, Artuner; Bayam, Mustafa; Onur, Ece; Onan, Arzu; Cam, Fethi S

2017-01-01

Brain-derived neurotrophic factor (BDNF) gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA) samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.

Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus

PubMed Central

Coskunoglu, Aysun; Orenay-Boyacioglu, Seda; Deveci, Artuner; Bayam, Mustafa; Onur, Ece; Onan, Arzu; Cam, Fethi S.

2017-01-01

Background: Brain-derived neurotrophic factor (BDNF) gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. Materials and Methods: In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA) samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. Results: Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. Conclusions: This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results. PMID:28615544

Ser46 phosphorylation and prolyl-isomerase Pin1-mediated isomerization of p53 are key events in p53-dependent apoptosis induced by mutant huntingtin

PubMed Central

Grison, Alice; Mantovani, Fiamma; Comel, Anna; Agostoni, Elena; Gustincich, Stefano; Persichetti, Francesca; Del Sal, Giannino

2011-01-01

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for huntingtin protein. Several mechanisms have been proposed by which mutant huntingtin (mHtt) may trigger striatal neurodegeneration, including mitochondrial dysfunction, oxidative stress, and apoptosis. Furthermore, mHtt induces DNA damage and activates a stress response. In this context, p53 plays a crucial role in mediating mHtt toxic effects. Here we have dissected the pathway of p53 activation by mHtt in human neuronal cells and in HD mice, with the aim of highlighting critical nodes that may be pharmacologically manipulated for therapeutic intervention. We demonstrate that expression of mHtt causes increased phosphorylation of p53 on Ser46, leading to its interaction with phosphorylation-dependent prolyl isomerase Pin1 and consequent dissociation from the apoptosis inhibitor iASPP, thereby inducing the expression of apoptotic target genes. Inhibition of Ser46 phosphorylation by targeting homeodomain-interacting protein kinase 2 (HIPK2), PKCδ, or ataxia telangiectasia mutated kinase, as well as inhibition of the prolyl isomerase Pin1, prevents mHtt-dependent apoptosis of neuronal cells. These results provide a rationale for the use of small-molecule inhibitors of stress-responsive protein kinases and Pin1 as a potential therapeutic strategy for HD treatment. PMID:22011578

Molecular Therapy of Melanocortin-4-Receptor Obesity by an Autoregulatory BDNF Vector.

PubMed

Siu, Jason J; Queen, Nicholas J; Liu, Xianglan; Huang, Wei; McMurphy, Travis; Cao, Lei

2017-12-15

Mutations in the melanocortin-4-receptor ( MC4R ) comprise the most common monogenic form of severe early-onset obesity, and conventional treatments are either ineffective long-term or contraindicated. Immediately downstream of MC4R-in the pathway for regulating energy balance-is brain-derived neurotrophic factor (BDNF). Our previous studies show that adeno-associated virus (AAV)-mediated hypothalamic BDNF gene transfer alleviates obesity and diabetes in both diet-induced and genetic models. To facilitate clinical translation, we developed a built-in autoregulatory system to control therapeutic gene expression mimicking the body's natural feedback systems. This autoregulatory approach leads to a sustainable plateau of body weight after substantial weight loss is achieved. Here, we examined the efficacy and safety of autoregulatory BDNF gene therapy in Mc4r heterozygous mice, which best resemble MC4R obese patients. Mc4r heterozygous mice were treated with either autoregulatory BDNF vector or YFP control and monitored for 30 weeks. BDNF gene therapy prevented the development of obesity and metabolic syndromes characterized by decreasing body weight and adiposity, suppressing food intake, alleviating hyperleptinemia and hyperinsulinemia, improving glucose and insulin tolerance, and increasing energy expenditure, without adverse cardiovascular function or behavioral disturbances. These safety and efficacy data provide preclinical evidence that BDNF gene therapy is a compelling treatment option for MC4R -deficient obese patients.

Higher brain BDNF gene expression is associated with slower cognitive decline in older adults.

PubMed

Buchman, Aron S; Yu, Lei; Boyle, Patricia A; Schneider, Julie A; De Jager, Philip L; Bennett, David A

2016-02-23

We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in individuals with pathologic AD (p = 0.006), but was not associated with macroscopic infarcts, Lewy body disease, or hippocampal sclerosis. BDNF expression remained associated with cognitive decline in a model adjusting for age, sex, education, and neuropathologies (p < 0.001). Furthermore, the effect of AD pathology on cognitive decline varied by BDNF expression such that the effect was strongest for high levels of AD pathology (p = 0.015); thus, in individuals with high AD pathology (90th percentile), cognitive decline was about 40% slower with the 90th percentile BDNF expression vs 10th. Higher brain BDNF expression is associated with slower cognitive decline and may also reduce the deleterious effects of AD pathology on cognitive decline. © 2016 American Academy of Neurology.

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.

PubMed

Kalchman, M A; Koide, H B; McCutcheon, K; Graham, R K; Nichol, K; Nishiyama, K; Kazemi-Esfarjani, P; Lynn, F C; Wellington, C; Metzler, M; Goldberg, Y P; Kanazawa, I; Gietz, R D; Hayden, M R

1997-05-01

Huntington disease (HD) is associated with the expansion of a polyglutamine tract, greater than 35 repeats, in the HD gene product, huntingtin. Here we describe a novel huntingtin interacting protein, HIP1, which co-localizes with huntingtin and shares sequence homology and biochemical characteristics with Sla2p, a protein essential for function of the cytoskeleton in Saccharomyces cerevisiae. The huntingtin-HIP1 interaction is restricted to the brain and is inversely correlated to the polyglutamine length in huntingtin. This provides the first molecular link between huntingtin and the neuronal cytoskeleton and suggests that, in HD, loss of normal huntingtin-HIP1 interaction may contribute to a defect in membrane-cytoskeletal integrity in the brain.

The Neuroprotective Effect of Curcumin Against Nicotine-Induced Neurotoxicity is Mediated by CREB-BDNF Signaling Pathway.

PubMed

Motaghinejad, Majid; Motevalian, Manijeh; Fatima, Sulail; Faraji, Fahimeh; Mozaffari, Shiva

2017-10-01

Nicotine abuse adversely affects brain and causes apoptotic neurodegeneration. Curcumin- a bright yellow chemical compound found in turmeric is associated with neuroprotective properties. The current study was designed to evaluate the role of CREB-BDNF signaling in mediating the neuroprotective effects of curcumin against nicotine-induced apoptosis, oxidative stress and inflammation in rats. Sixty adult male rats were divided randomly into six groups. Group 1 received 0.7 ml/rat normal saline, group 2 received 6 mg/kg nicotine. Groups 3, 4, 5 and 6 were treated concurrently with nicotine (6 mg/kg) and curcumin (10, 20, 40 and 60 mg/kg i.p. respectively) for 21 days. Open Field Test (OFT) was used to evaluate the motor activity. Hippocampal oxidative, anti-oxidant, inflammatory and apoptotic factors were evaluated. Furthermore, phosphorylated brain cyclic adenosine monophosphate (cAMP) response element binding protein (P-CREB) and brain derived neurotrophic factor (BDNF) levels were studied at gene and protein levels. We found that nicotine disturbed the motor activity in OFT and simultaneous treatment with curcumin (40 and 60 mg/kg) reduced the nicotine-induced motor activity disturbances. In addition, nicotine treatment increased lipid peroxidation and the levels of GSH, IL-1β, TNF-α and Bax, while reducing Bcl-2, P-CREB and BDNF levels in the hippocampus. Nicotine also reduced the activity of superoxide dismutase, glutathione peroxidase and glutathione reductase in hippocampus. In contrast, various doses of curcumin attenuated nicotine-induced apoptosis, oxidative stress and inflammation; while elevating P-CREB and BDNF levels. Thus, curcumin via activation of P-CREB/BDNF signaling pathway, confers neuroprotection against nicotine-induced inflammation, apoptosis and oxidative stress.

Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency.

PubMed

Katsu-Jiménez, Yurika; Loría, Frida; Corona, Juan Carlos; Díaz-Nido, Javier

2016-05-01

Friedreich's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). Here, we have used a herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) to drive its overexpression in neuronal cells and test for its effect on FXN-deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of FXN gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for a FXN-specific short hairpin ribonucleic acid (shRNA) into the mouse cerebellar cortex triggers a FXN deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These pathological changes are accompanied by a loss of motor coordination of mice as assayed by the rota-rod test. Coinjection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration.

HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity.

PubMed

Mattis, Virginia B; Tom, Colton; Akimov, Sergey; Saeedian, Jasmine; Østergaard, Michael E; Southwell, Amber L; Doty, Crystal N; Ornelas, Loren; Sahabian, Anais; Lenaeus, Lindsay; Mandefro, Berhan; Sareen, Dhruv; Arjomand, Jamshid; Hayden, Michael R; Ross, Christopher A; Svendsen, Clive N

2015-06-01

Huntington's disease (HD) is a fatal neurodegenerative disease, caused by expansion of polyglutamine repeats in the Huntingtin gene, with longer expansions leading to earlier ages of onset. The HD iPSC Consortium has recently reported a new in vitro model of HD based on the generation of induced pluripotent stem cells (iPSCs) from HD patients and controls. The current study has furthered the disease in a dish model of HD by generating new non-integrating HD and control iPSC lines. Both HD and control iPSC lines can be efficiently differentiated into neurons/glia; however, the HD-derived cells maintained a significantly greater number of nestin-expressing neural progenitor cells compared with control cells. This cell population showed enhanced vulnerability to brain-derived neurotrophic factor (BDNF) withdrawal in the juvenile-onset HD (JHD) lines, which appeared to be CAG repeat-dependent and mediated by the loss of signaling from the TrkB receptor. It was postulated that this increased death following BDNF withdrawal may be due to glutamate toxicity, as the N-methyl-d-aspartate (NMDA) receptor subunit NR2B was up-regulated in the cultures. Indeed, blocking glutamate signaling, not just through the NMDA but also mGlu and AMPA/Kainate receptors, completely reversed the cell death phenotype. This study suggests that the pathogenesis of JHD may involve in part a population of 'persistent' neural progenitors that are selectively vulnerable to BDNF withdrawal. Similar results were seen in adult hippocampal-derived neural progenitors isolated from the BACHD model mouse. Together, these results provide important insight into HD mechanisms at early developmental time points, which may suggest novel approaches to HD therapeutics. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

PubMed Central

Sakata, Kazuko; Martinowich, Keri; Woo, Newton H.; Schloesser, Robert J.; Jimenez, Dennisse V.; Ji, Yuanyuan; Shen, Liya; Lu, Bai

2013-01-01

Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal–PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders. PMID:23980178

Blocking GSK3β-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer's disease.

PubMed

Liu, Xiang-Hua; Geng, Zhao; Yan, Jing; Li, Ting; Chen, Qun; Zhang, Qun-Ye; Chen, Zhe-Yu

2015-02-01

Endocytosis of tropomyosin related kinase B (TrkB) receptors has critical roles in brain-derived neurotrophic factor (BDNF) mediated signal transduction and biological function, however the mechanism that is governing TrkB endocytosis is still not completely understood. In this study, we showed that GSK3β, a key kinase in neuronal development and survival, could regulate TrkB endocytosis through phosphorylating dynamin1 (Dyn1) but not dynamin2 (Dyn2). Moreover, we found that beta-amyloid (Aβ) oligomer exposure could impair BDNF-dependent TrkB endocytosis and Akt activation through enhancing GSK3β activity in cultured hippocampal neurons, which suggested that BDNF-induced TrkB endocytosis and the subsequent signaling were impaired in neuronal model of Alzheimer's disease (AD). Notably, we found that inhibiting GSK3β phosphorylating Dyn1 by using TAT-Dyn1SpS could rescue the impaired TrkB endocytosis and Akt activation upon BDNF stimuli under Aβ exposure. Finally, TAT-Dyn1SpS could facilitate BDNF-mediated neuronal survival and cognitive enhancement in mouse models of AD. These results clarified a role of GSK3β in BDNF-dependent TrkB endocytosis and the subsequent signaling, and provided a potential new strategy by inhibiting GSK3β-induced Dyn1 phosphorylation for AD treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding.

PubMed

Gourley, Shannon L; Swanson, Andrew M; Jacobs, Andrea M; Howell, Jessica L; Mo, Michelle; Dileone, Ralph J; Koleske, Anthony J; Taylor, Jane R

2012-12-11

Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.

The BDNF/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats.

PubMed

Zhang, Hong-Hai; Zhang, Xiao-Qin; Xue, Qing-Sheng; Yan-Luo; Huang, Jin-Lu; Zhang, Su; Shao, Hai-Jun; Lu, Han; Wang, Wen-Yuan; Yu, Bu-Wei

2014-01-01

Cyclin-dependent kinase 5 (Cdk5) has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) via the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway in the dorsal horn of the spinal cord in rats. Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co-immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine. Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain.

HIP12 is a non-proapoptotic member of a gene family including HIP1, an interacting protein with huntingtin.

PubMed

Chopra, V S; Metzler, M; Rasper, D M; Engqvist-Goldstein, A E; Singaraja, R; Gan, L; Fichter, K M; McCutcheon, K; Drubin, D; Nicholson, D W; Hayden, M R

2000-11-01

Huntingtin-interacting protein I (HIP1) is a membrane-associated protein that interacts with huntingtin, the protein altered in Huntington disease. HIP1 shows homology to Sla2p, a protein essential for the assembly and function of the cytoskeleton and endocytosis in Saccharomyces cerevisiae. We have determined that the HIP1 gene comprises 32 exons spanning approximately 215 kb of genomic DNA and gives rise to two alternate splice forms termed HIP1-1 and HIP1-2. Additionally, we have identified a novel protein termed HIP12 with significant sequence and biochemical similarities to HIP1 and high sequence similarity to Sla2p. HIP12 differs from HIP1 in its pattern of expression both at the mRNA and protein level. However, HIP1 and HIP12 are both found within the brain and show a similar subcellular distribution pattern. In contrast to HIP1, which is toxic in cell culture, HIP12 does not confer toxicity in the same assay systems. Interestingly, HIP12 does not interact with huntingtin but can interact with HIP1. suggesting a potential interaction in vivo that may influence the function of each respective protein.

BDNF function as a potential mediator of bipolar disorder and post-traumatic stress disorder comorbidity

PubMed Central

Rakofsky, JJ; Ressler, KJ; Dunlop, BW

2013-01-01

Bipolar disorder (BD) and post-traumatic stress disorder (PTSD) frequently co-occur among psychiatric patients, leading to increased morbidity and mortality. Brain-derived neurotrophic factor (BDNF) function is associated with core characteristics of both BD and PTSD. We propose a neurobiological model that underscores the role of reduced BDNF function resulting from several contributing sources, including the met variant of the BDNF val66met (rs6265) single-nucleotide polymorphism, trauma-induced epigenetic regulation and current stress, as a contributor to the onset of both illnesses within the same person. Further studies are needed to evaluate the genetic association between the val66met allele and the BD-PTSD population, along with central/peripheral BDNF levels and epigenetic patterns of BDNF gene regulation within these patients. PMID:21931317

Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons

PubMed Central

2011-01-01

Background Huntington's disease is caused by aggregation of mutant huntingtin (mHtt) protein containing more than a 36 polyQ repeat. Upregulation of macroautophagy was suggested as a neuroprotective strategy to degrade mutant huntingtin. However, macroautophagy initiation has been shown to be highly efficient in neurons whereas lysosomal activities are rate limiting. The role of the lysosomal and other proteases in Huntington is not clear. Some studies suggest that certain protease activities may contribute to toxicity whereas others are consistent with protection. These discrepancies may be due to a number of mechanisms including distinct effects of the specific intermediate digestion products of mutant huntingtin generated by different proteases. These observations suggested a critical need to investigate the consequence of upregulation of individual lysosomal enzyme in mutant huntingtin accumulation and toxicity. Results In this study, we used molecular approaches to enhance lysosomal protease activities and examined their effects on mutant huntingtin level and toxicity. We found that enhanced expression of lysosomal cathepsins D and B resulted in their increased enzymatic activities and reduced both full-length and fragmented huntingtin in transfected HEK cells. Furthermore, enhanced expression of cathepsin D or B protected against mutant huntingtin toxicity in primary neurons, and their neuroprotection is dependent on macroautophagy. Conclusions These observations demonstrate a neuroprotective effect of enhancing lysosomal cathepsins in reducing mutant huntingtin level and toxicity in transfected cells. They highlight the potential importance of neuroprotection mediated by cathepsin D or B through macroautophagy. PMID:21631942

Epigenetic alterations of the BDNF gene in combat-related post-traumatic stress disorder.

PubMed

Kim, T Y; Kim, S J; Chung, H G; Choi, J H; Kim, S H; Kang, J I

2017-02-01

Brain-derived neurotrophic factor (BDNF) plays a crucial role in modulating resilience and vulnerability to stress. The aim of this study was to investigate whether epigenetic regulation of the BDNF gene is a biomarker of post-traumatic stress disorder (PTSD) development among veterans exposed to combat in the Vietnam War. Using the Clinician-Administered PTSD Scale, combat veterans were grouped into those with (n = 126) and without (n = 122) PTSD. DNA methylation levels at four CpG sites within the BDNF promoter I region were quantified in the peripheral blood using pyrosequencing. The effects of BDNF DNA methylation levels and clinical variables on the diagnosis of PTSD were tested using binary logistic regression analysis. Subjects with PTSD showed a higher DNA methylation of four CpG sites at the BDNF promoter compared with those without PTSD. High methylation levels at the BDNF promoter CpG site, high combat exposure, and alcohol problems were significantly associated with PTSD diagnosis. This study demonstrated an association between higher DNA methylation of the BDNF promoter and PTSD diagnosis in combat-exposed individuals. Our findings suggest that altered BDNF methylation may be a valuable biomarker of PTSD after trauma exposure. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation

PubMed Central

Wang, Jin; Gines, Silvia; MacDonald, Marcy E; Gusella, James F

2005-01-01

Background Huntington's disease (HD) is an inherited neurodegenerative disorder triggered by an expanded polyglutamine tract in huntingtin that is thought to confer a new conformational property on this large protein. The propensity of small amino-terminal fragments with mutant, but not wild-type, glutamine tracts to self-aggregate is consistent with an altered conformation but such fragments occur relatively late in the disease process in human patients and mouse models expressing full-length mutant protein. This suggests that the altered conformational property may act within the full-length mutant huntingtin to initially trigger pathogenesis. Indeed, genotype-phenotype studies in HD have defined genetic criteria for the disease initiating mechanism, and these are all fulfilled by phenotypes associated with expression of full-length mutant huntingtin, but not amino-terminal fragment, in mouse models. As the in vitro aggregation of amino-terminal mutant huntingtin fragment offers a ready assay to identify small compounds that interfere with the conformation of the polyglutamine tract, we have identified a number of aggregation inhibitors, and tested whether these are also capable of reversing a phenotype caused by endogenous expression of mutant huntingtin in a striatal cell line from the HdhQ111/Q111 knock-in mouse. Results We screened the NINDS Custom Collection of 1,040 FDA approved drugs and bioactive compounds for their ability to prevent in vitro aggregation of Q58-htn 1–171 amino terminal fragment. Ten compounds were identified that inhibited aggregation with IC50 < 15 μM, including gossypol, gambogic acid, juglone, celastrol, sanguinarine and anthralin. Of these, both juglone and celastrol were effective in reversing the abnormal cellular localization of full-length mutant huntingtin observed in mutant HdhQ111/Q111 striatal cells. Conclusions At least some compounds identified as aggregation inhibitors also prevent a neuronal cellular phenotype caused

Elevated Serum Brain-Derived Neurotrophic Factor (BDNF) but not BDNF Gene Val66Met Polymorphism Is Associated with Autism Spectrum Disorders.

PubMed

Meng, Wei-Dong; Sun, Shao-Jun; Yang, Jie; Chu, Rui-Xue; Tu, Wenjun; Liu, Qiang

2017-03-01

The aim of our study was to illuminate the potential role of brain-derived neurotrophic factor (BDNF) in autism spectrum disorder (ASD). We measured the circulating levels of BDNF in serum and BDNF gene (Val66Met) polymorphisms, in which two indicators were then compared between ASD and normal controls. A total of 82 drug-naïve ASD children and 82 age- and gender-matched normal controls were enrolled in the study. Their serum BDNF levels were detected by the ELISA. BDNF Val66Met polymorphism genotyping was conducted as according to the laboratory's standard protocol in laboratory. The ASD severity assessment was mainly determined by the score of the Childhood Autism Rating Scale (CARS). ELISA assay showed that the mean serum BDNF level of children with ASD was significantly (P < 0.0001) higher than that of the control cases (17.75 ± 5.43 vs. 11.49 ± 2.85 ng/ml; t = 9.236). Besides, the serum BDNF levels and CARS scores (P < 0.0001) were positively related. And, the BDNF genotyping results showed that there was no difference between the ASD cases and the control. Among the children with ASD, the mean serum BDNF level of Met/Met group was lower than other groups. According to the ROC curve generated from our clinical data, the optimal cutoff value of serum BDNF levels, an indicator for diagnosis of ASD, was projected to be 12.50 ng/ml. Thus, it yielded a corresponding sensitivity of 81.7 % and the specificity of 66.9 %. Accordingly, area value under the curve was 0.836 (95 % CI, 0.774-0.897); the positive predictive value (PPV) and the negative predictive value (NPV) were 70.1 and 79.1 %, respectively. These results suggested that rather than Val66Met polymorphism, BDNF was more possible to impact the pathogenesis of ASD.

Huntingtin interacting protein 1 can regulate neurogenesis in Drosophila.

PubMed

Moores, Justin N; Roy, Sophie; Nicholson, Donald W; Staveley, Brian E

2008-08-01

Huntington's disease (HD) is associated with a range of cellular consequences including selective neuronal death and decreased levels of neurogenesis. Ultimately, these altered processes are dependent upon proteins that interact with Huntingtin (Htt) such as the Huntingtin-interacting protein 1 (Hip1) which has a reduced binding preference to expanded Htt. These effects are similar to those observed with modified Notch signal transduction. As Hip1 plays a key role in endocytosis and intracellular transport, and activation of the Notch signal requires both, we investigated putative links between Hip1 and Notch signaling in flies. We have identified two forms of Hip1 that may be produced through the use of alternative first exons: a version of Hip1 with a lipid-binding ANTH domain and Hip1DeltaANTH lacking this domain. The directed expression of Hip1 decreases, while expression of Hip1DeltaANTH increases, the density of sensory microchaetae on the dorsal notum, a classical model of neurogenesis. A reduction in microchaetae density associated with Notch(Microchaetae Deficient (MCD)) (N(MCD) ) alleles is sensitive to both Hip1 and Hip1DeltaANTH levels, as are the bristle phenotypes generated by misexpression of deltex, a key mediator of Notch signaling. Genetic studies further demonstrate that the observed effects of Hip1 and of Hip1DeltaANTH are sensitive to achaete gene dosage while insensitive to the levels of E(Spl), suggesting a non-canonical Notch neurogenic signal through a deltex-dependent pathway. The novel role we describe for Hip1 in Notch-mediated neurogenesis provides a functional link between Notch signaling and proteins related to HD.

Promoter Methylation and BDNF and DAT1 Gene Expression Profiles in Patients with Drug Addiction.

PubMed

Kordi-Tamandani, Dor Mohammad; Tajoddini, Shahrad; Salimi, Farzaneh

2015-01-01

Drug addiction is a brain disorder that has negative consequences for individuals and society. Addictions are chronic relapsing diseases of the brain that are caused by direct drug-induced effects and persevering neuroadaptations at the epigenetic, neuropeptide and neurotransmitter levels. Because the dopaminergic system has a significant role in drug abuse, the purpose of this study was to analyze the methylation and expression profile of brain-derived neurotrophic factor (BDNF) and dopamine transporter (DAT1) genes in individuals with drug addiction. BDNF and DAT1 promoter methylation were investigated with a methylation-specific polymerase chain reaction (PCR) technique in blood samples from 75 individuals with drug addiction and 65 healthy controls. The expression levels of BDNF and DAT1 were assessed in 12 mRNA samples from the blood of patients and compared to the samples of healthy controls (n = 12) with real-time quantitative reverse transcription PCR. No significant differences were found in the methylation of BDNF and DAT1 between patients and controls, but the relative levels of expression of BDNF and DAT1 mRNA differed significantly in the patients compared to controls (p < 0.0001). These results showed that the methylation status of the BDNF and DAT1 genes had no significant function in the processes of drug addiction.

Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats.

PubMed

Chao, Yu-Chieh; Xie, Fang; Li, Xueyang; Guo, Ruijuan; Yang, Ning; Zhang, Chen; Shi, Rong; Guan, Yun; Yue, Yun; Wang, Yun

2016-07-01

Repeated administration of morphine may result in opioid-induced hypersensitivity (OIH), which involves altered expression of numerous genes, including brain-derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) neurons. Yet, it remains unclear how BDNF expression is increased in DRG neurons after repeated morphine treatment. DNA methylation is an important mechanism of epigenetic control of gene expression. In the current study, we hypothesized that the demethylation regulation of certain BDNF gene promoters in DRG neurons may contribute to the development of OIH. Real-time RT-PCR was used to assess changes in the mRNA transcription levels of major BDNF exons including exon I, II, IV, VI, as well as total BDNF mRNA in DRGs from rats after repeated morphine administration. The levels of exon IV and total BDNF mRNA were significantly upregulated by repeated morphine administration, as compared to that in saline control group. Further, ELISA array and immunocytochemistry study revealed a robust upregulation of BDNF protein expression in DRG neurons after repeated morphine exposure. Correspondingly, the methylation levels of BDNF exon IV promoter showed a significant downregulation by morphine treatment. Importantly, intrathecal administration of a BDNF antibody, but not control IgG, significantly inhibited mechanical hypersensitivity that developed in rats after repeated morphine treatment. Conversely, intrathecal administration of an inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-aza-dC) markedly upregulated the BDNF protein expression in DRG neurons and enhanced the mechanical allodynia after repeated morphine exposure. Together, our findings suggest that demethylation regulation of BDNF gene promoter may be implicated in the development of OIH through epigenetic control of BDNF expression in DRG neurons. Copyright © 2016 Elsevier Ltd. All rights reserved.

Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor to bone marrow stromal cells promotes axonal regeneration after transplantation in completely transected adult rat spinal cord

PubMed Central

Kamada, Takahito; Hashimoto, Masayuki; Murakami, Masazumi; Shirasawa, Hiroshi; Sakao, Seiichiro; Ino, Hidetoshi; Yoshinaga, Katsunori; Koshizuka, Shuhei; Moriya, Hideshige; Yamazaki, Masashi

2007-01-01

The aim of this study was to evaluate the efficacy in adult rat completely transected spinal cord of adenovirus vector-mediated brain-derived neurotrophic factor (BDNF) ex vivo gene transfer to bone marrow stromal cells (BMSC). BMSC were infected with adenovirus vectors carrying β-galactosidase (AxCALacZ) or BDNF (AxCABDNF) genes. The T8 segment of spinal cord was removed and replaced by graft containing Matrigel alone (MG group) or Matrigel and BMSC infected by AxCALacZ (BMSC-LacZ group) or AxCABDNF (BMSC-BDNF group). Axons in the graft were evaluated by immunohistochemistry and functional recovery was assessed with BBB locomotor scale. In the BMSC-BDNF group, the number of fibers positive for growth associated protein-43, tyrosine hydroxylase, and calcitonin gene-related peptide was significantly larger than numbers found for the MG and BMSC-LacZ groups. Rats from BMSC-BDNF and BMSC-LacZ groups showed significant recovery of hind limb function compared with MG rats; however, there was no significant difference between groups in degree of functional recovery. These findings demonstrate that adenovirus vector-mediated ex vivo gene transfer of BDNF enhances the capacity of BMSC to promote axonal regeneration in this completely transected spinal cord model; however, BDNF failed to enhance hind limb functional recovery. Further investigation is needed to establish an optimal combination of cell therapy and neurotrophin gene transfer for cases of spinal cord injury. PMID:17885772

Association study between BDNF gene variants and Mexican patients with obsessive-compulsive disorder.

PubMed

Márquez, Lidia; Camarena, Beatriz; Hernández, Sandra; Lóyzaga, Cristina; Vargas, Luis; Nicolini, Humberto

2013-11-01

Obsessive-compulsive disorder (OCD) is a psychiatric disorder whose etiology is not yet known. We investigate the role of three variants of the BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and haplotype analysis in OCD Mexican patients using a case-control and family-based association design. BDNF gene variants were genotyped in 283 control subjects, 232 OCD patients and first degree relatives of 111 OCD subjects. Single SNP analysis in case-control study showed an association between rs6265 and OCD with a high frequency of Val/Val genotype and Val allele (p=0.0001 and p=0.0001, respectively). Also, genotype and allele analysis of rs1519480 showed significant differences (p=0.0001, p=0.0001; respectively) between OCD and control groups. Haplotype analysis showed a high frequency of A-T (rs6265-rs1519480) in OCD patients compared with the control group (OR=2.06 [1.18-3.59], p=0.0093) and a low frequency of haplotype A-C in the OCD patients (OR=0.04 [0.01-0.16], p=0.000002). The family-based association study showed no significant differences in the transmission of any variant. Our study replicated the association between BDNF Val66Met gene polymorphism and OCD. Also, we found a significant association of rs1519480 in OCD patients compared with a control group, region that has never been analyzed in OCD. In conclusion, our findings suggest that BDNF gene could be related to the development of OCD. © 2013 Elsevier B.V. and ECNP. All rights reserved.

Tyrosine triple mutated AAV2-BDNF gene therapy in a rat model of transient IOP elevation

PubMed Central

Igarashi, Tsutomu; Kobayashi, Maika; Kameya, Shuhei; Fujimoto, Chiaki; Nakamoto, Kenji; Takahashi, Hisatomo; Igarashi, Toru; Miyake, Noriko; Iijima, Osamu; Hirai, Yukihiko; Shimada, Takashi; Okada, Takashi; Takahashi, Hiroshi

2016-01-01

Purpose We examined the neuroprotective effects of exogenous brain-derived neurotrophic factor (BDNF), which provides protection to retinal ganglion cells (RGCs) in rodents, in a model of transient intraocular pressure (IOP) elevation using a mutant (triple Y-F) self-complementary adeno-associated virus type 2 vector encoding BDNF (tm-scAAV2-BDNF). Methods The tm-scAAV2-BDNF or control vector encoding green fluorescent protein (GFP; tm-scAAV2-GFP) was intravitreally administered to rats, which were then divided into four groups: control, ischemia/reperfusion (I/R) injury only, I/R injury with tm-scAAV2-GFP, and tm-scAAV2-BDNF. I/R injury was then induced by transiently increasing IOP, after which the rats were euthanized to measure the inner retinal thickness and cell counts in the RGC layer. Results Intravitreous injection of tm-scAAV2-BDNF resulted in high levels of BDNF expression in the neural retina. Histological analysis showed that the inner retinal thickness and cell numbers in the RGC layer were preserved after transient IOP elevation in eyes treated with tm-scAAV2-BDNF but not in the other I/R groups. Significantly reduced glial fibrillary acidic protein (GFAP) immunostaining after I/R injury in the rats that received tm-scAAV2-BDNF indicated reduced retinal stress, and electroretinogram (ERG) analysis confirmed preservation of retinal function in the tm-scAAV2-BDNF group. Conclusions These results demonstrate the feasibility and effectiveness of neuroprotective gene therapy using tm-scAAV2-BDNF to protect the inner retina from transiently high intraocular pressure. An in vivo gene therapeutic approach to the clinical management of retinal diseases in conditions such as glaucoma, retinal artery occlusion, hypertensive retinopathy, and diabetic retinopathy thus appears feasible. PMID:27440998

Huntingtin coordinates the dynein-mediated dynamic positioning of endosomes and lysosomes

PubMed Central

Caviston, Juliane P.; Zajac, Allison L.; Tokito, Mariko; Holzbaur, Erika L.F.

2011-01-01

Huntingtin (Htt) is a membrane-associated scaffolding protein that interacts with microtubule motors as well as actin-associated adaptor molecules. We examined a role for Htt in the dynein-mediated intracellular trafficking of endosomes and lysosomes. In HeLa cells depleted of either Htt or dynein, early, recycling, and late endosomes (LE)/lysosomes all become dispersed. Despite altered organelle localization, kinetic assays indicate only minor defects in intracellular trafficking. Expression of full-length Htt is required to restore organelle localization in Htt-depleted cells, supporting a role for Htt as a scaffold that promotes functional interactions along its length. In dynein-depleted cells, LE/lysosomes accumulate in tight patches near the cortex, apparently enmeshed by cortactin-positive actin filaments; Latrunculin B-treatment disperses these patches. Peripheral LE/lysosomes in dynein-depleted cells no longer colocalize with microtubules. Htt may be required for this off-loading, as the loss of microtubule association is not seen in Htt-depleted cells or in cells depleted of both dynein and Htt. Inhibition of kinesin-1 relocalizes peripheral LE/lysosomes induced by Htt depletion but not by dynein depletion, consistent with their detachment from microtubules upon dynein knockdown. Together, these data support a model of Htt as a facilitator of dynein-mediated trafficking that may regulate the cytoskeletal association of dynamic organelles. PMID:21169558

Real-time imaging of Huntingtin aggregates diverting target search and gene transcription

PubMed Central

Li, Li; Liu, Hui; Dong, Peng; Li, Dong; Legant, Wesley R; Grimm, Jonathan B; Lavis, Luke D; Betzig, Eric; Tjian, Robert; Liu, Zhe

2016-01-01

The presumptive altered dynamics of transient molecular interactions in vivo contributing to neurodegenerative diseases have remained elusive. Here, using single-molecule localization microscopy, we show that disease-inducing Huntingtin (mHtt) protein fragments display three distinct dynamic states in living cells – 1) fast diffusion, 2) dynamic clustering and 3) stable aggregation. Large, stable aggregates of mHtt exclude chromatin and form 'sticky' decoy traps that impede target search processes of key regulators involved in neurological disorders. Functional domain mapping based on super-resolution imaging reveals an unexpected role of aromatic amino acids in promoting protein-mHtt aggregate interactions. Genome-wide expression analysis and numerical simulation experiments suggest mHtt aggregates reduce transcription factor target site sampling frequency and impair critical gene expression programs in striatal neurons. Together, our results provide insights into how mHtt dynamically forms aggregates and disrupts the finely-balanced gene control mechanisms in neuronal cells. DOI: http://dx.doi.org/10.7554/eLife.17056.001 PMID:27484239

A functional brain-derived neurotrophic factor (BDNF) gene variant increases the risk of moderate-to-severe allergic rhinitis.

PubMed

Jin, Peng; Andiappan, Anand Kumar; Quek, Jia Min; Lee, Bernett; Au, Bijin; Sio, Yang Yie; Irwanto, Astrid; Schurmann, Claudia; Grabe, Hans Jörgen; Suri, Bani Kaur; Matta, Sri Anusha; Westra, Harm-Jan; Franke, Lude; Esko, Tonu; Sun, Liangdan; Zhang, Xuejun; Liu, Hong; Zhang, Furen; Larbi, Anis; Xu, Xin; Poidinger, Michael; Liu, Jianjun; Chew, Fook Tim; Rotzschke, Olaf; Shi, Li; Wang, De Yun

2015-06-01

Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. We sought to identify disease associations and the functional effect of BDNF genetic variants in patients with moderate-to-severe AR. Tagging single nucleotide polymorphisms (SNPs) spanning the BDNF gene were selected from the human HapMap Han Chinese from Beijing (CHB) data set, and associations with moderate-to-severe AR were assessed in 2 independent cohorts of Chinese patients (2216 from Shandong province and 1239 living in Singapore). The functional effects of the BDNF genetic variants were determined by using both in vitro and ex vivo assays. The tagging SNP rs10767664 was significantly associated with the risk of moderate-to-severe AR in both Singapore Chinese (P = .0017; odds ratio, 1.324) and Shandong Chinese populations (P = .039; odds ratio, 1.180). The coding nonsynonymous SNP rs6265 was in perfect linkage with rs10767664 and conferred increased BDNF protein secretion by a human cell line in vitro. Subjects bearing the AA genotype of rs10767664 exhibited increased risk of moderate-to-severe AR and displayed increased BDNF protein and total IgE levels in plasma. Using a large-scale expression quantitative trait locus study, we demonstrated that BDNF SNPs are significantly associated with altered BDNF concentrations in peripheral blood. A common genetic variant of the BDNF gene is associated with increased risk of moderate-to-severe AR, and the AA genotype is associated with increased BDNF mRNA levels in peripheral blood. Together, these data indicate that functional BDNF gene variants increase the risk of moderate-to-severe AR. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The lighter side of BDNF

PubMed Central

Noble, Emily E.; Billington, Charles J.; Kotz, Catherine M.

2011-01-01

Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that “faulty” circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity. PMID:21346243

Rescue of photoreceptors by BDNF gene transfer using in vivo electroporation in the RCS rat of retinitis pigmentosa.

PubMed

Zhang, Meng; Mo, Xiaofen; Fang, Yuan; Guo, Wenyi; Wu, Jihong; Zhang, Shenghai; Huang, Qian

2009-09-01

To investigate the feasibility of introducing brain-derived neurotrophic factor (BDNF) gene into retinal pigment epithelial cells in vivo by electroporation and whether this method can rescue photoreceptors of retinitis pigmentosa in Royal College Surgeons (RCS) rats. The BDNF-GFP fusion eukaryotic-expressing plasmid was constructed and subretinally or intravitreously injected into the eyes of RCS rats followed by in vivo electroporation. The expression of BDNF mRNA and protein was detected by RT-PCR and Western immunoblot analysis. The number of surviving photoreceptors was counted, and the TdT-dUTP terminal nick-end labeling (TUNEL) method was used to detect the apoptotic retinal cells at different timepoints after introduction of BDNF plasmid. Treated eyes showed a significantly higher rescue ratio and a lower number of TUNEL-positive photoreceptors than did the control eyes at various timepoints. These findings provide evidence that electroporation is an effective method for gene transfer into retinal pigment epithelial cells, and the rescue of photoreceptors can be achieved by BDNF gene transfection with electroporation.

[Behavior in the forced-swimming test and expression of BDNF and Bcl-xl genes in the rat brain].

PubMed

Berezova, I V; Shishkina, G T; Kalinina, T S; Dygalo, N N

2011-01-01

A single exposure of rats to the forced-swimming stress decreased BDNF mRNA levels in the cortex and increased Bcl-xl gene expression in the hippocampus and amygdala 24 h after the stress. The animals demonstrated a depressive-like behavior and elevated blood corticosterone level. There was a significant negative correlation between BDNF mRNA level in the cortex and immobility time during swimming. Repeated exposure to swimming stress caused the elevation of the hippocampal BDNF mRNA level assessed 24 h after the second swimming session. The data suggest that stress-induced down-regulation of cortical BDNF gene expression and behavioral despair in the forced-swimming test may be interrelated. The increase in the BDNF and Bcl-xl mRNA levels may contribute to the mechanisms protecting the brain against negative effects of stress.

The Effects of BDNF Val66Met Gene Polymorphism on Serum BDNF and Cognitive Function in Methamphetamine-Dependent Patients and Normal Controls: A Case-Control Study.

PubMed

Su, Hang; Tao, Jingyan; Zhang, Jie; Xie, Ying; Wang, Yue; Zhang, Yu; Han, Bin; Lu, Yuling; Sun, Haiwei; Wei, Youdan; Zou, Shengzhen; Wu, Wenxiu; Zhang, Jiajia; Xu, Ke; Zhang, Xiangyang; He, Jincai

2015-10-01

Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may contribute to methamphetamine dependence. We hypothesized that this polymorphism had a role in cognitive deficits in methamphetamine-dependent patients and in the relationship of serum BDNF with cognitive impairments. We conducted a case-control study by assessing 194 methamphetamine-dependent patients and 378 healthy volunteers without history of drug use on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We showed no significant differences in genotype and allele distributions between the methamphetamine-dependent patients and controls. Some aspects of cognitive function significantly differed in the 2 groups. The serum BDNF levels in methamphetamine-dependent patients were significantly higher than those of the healthy controls. In the patients, partial correlation analysis showed a significant positive correlation between serum BDNF and the delayed memory index score. The RBANS scores showed statistically significant BDNF level × genotype interaction. Further regression analyses showed a significant positive association between BDNF levels and the RBANS total score, immediate memory or attention index among Val homozygote patients, whereas a significant negative association of BDNF levels with the RBANS total score, visuospatial/constructional, or language index was found among Met/Val heterozygous patients. We demonstrated significant impairment on some aspects of cognitive function and increased BDNF levels in methamphetamine-dependent patients as well as genotypic differences in the relationships between BDNF levels and RBANS scores on the BDNF Val66Met polymorphism only in these patients.

Association of BDNF gene polymorphisms with schizophrenia and clinical symptoms in a Chinese population.

PubMed

Li, Wenjun; Zhou, Na; Yu, Qiong; Li, Xiaokun; Yu, Yaqin; Sun, Shilong; Kou, Changgui; Chen, Da Chun; Xiu, Mei Hong; Kosten, Thomas R; Zhang, Xiang Yang

2013-09-01

The neurodevelopmental hypothesis is well established in schizophrenia. Accumulating evidence has shown that BDNF may be involved in the pathogenesis of schizophrenia. This study aimed to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and with the psychopathological symptoms in patients with schizophrenia in a Han Chinese population. Three polymorphisms (rs6265, rs12273539, and rs10835210) of the BDNF gene were analyzed in a case-control study of 709 Han Chinese individuals (375 patients and 334 controls). The patients' psychopathology was assessed using the positive and negative syndrome scale (PANSS). We found no significant differences in the genotype and allele distributions of all three polymorphisms between the patient and control groups; however, we found a trend toward to significant overall difference in the estimated haplotype frequencies, with more frequent haplotype ATC of rs6265-rs12273539-rs10835210 in the schizophrenic patients than in controls (P = 0.027). The quantitative trait analysis by the UNPHASED program showed significant associations between the rs6265 (A)-rs12273539 (C)-rs10835210 (A) haplotype and negative symptom scores from the PANSS (x(2)  = 5.79, P = 0.016). Our findings suggest that the BDNF gene polymorphisms may play a small effect on susceptibility to schizophrenia, but may contribute to the negative symptoms of the disease. Copyright © 2013 Wiley Periodicals, Inc.

BDNF-mediates Down-regulation of MicroRNA-195 Inhibits Ischemic Cardiac Apoptosis in Rats

PubMed Central

Hang, Pengzhou; Sun, Chuan; Guo, Jing; Zhao, Jing; Du, Zhimin

2016-01-01

Background: Our previous studies suggested that brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) axis inhibited cardiomyocyte apoptosis in myocardial infarction (MI). However, the relationship between BDNF and microRNA (miRNA) in cardiomyocytes are unclear. The present study was performed to investigate the role of miR-195 and the interplay between BDNF and miR-195 in ischemic cardiomyocyte apoptosis. Methods: Male Wistar rats were subjected to coronary artery ligation, and primary neonatal rat ventricular myocytes were treated with hypoxia or hydrogen peroxide (H2O2). BDNF level in rat ventricles was measured by enzyme linked immunosorbent assay (ELISA). miR-195 mimic, inhibitor or negative control was transfected into the cardiomyocytes. Cell viability and apoptosis were detected by MTT assay and TdT-mediated dUTP nick end labeling (TUNEL) staining, respectively. Cardiac function and apoptosis were detected in MI rats intravenously injected with antagomiR-195. Luciferase assay, Western blot and Real-time RT-PCR were employed to clarify the interplay between miR-195 and BDNF. Results: miR-195 level was dynamically regulated in response to MI and significantly increased in ischemic regions 24 h post-MI as well as in hypoxic or H2O2-treated cardiomyocytes. Meanwhile, BDNF protein level was rapidly increased in MI rats and H2O2-treated cardiomyocytes. Apoptosis in both hypoxic and H2O2-treated cardiomyocytes were markedly reduced and cell viability was increased by miR-195 inhibitor. Moreover, inhibition of miR-195 significantly improved cardiac function of MI rats. Bcl-2 but not BDNF was validated as the direct target of miR-195. Furthermore, BDNF abolished the pro-apoptotic role of miR-195, which was reversed by its scavenger TrkB-Fc. Conclusion: Up-regulation of miR-195 in ischemic cardiomyocytes promotes ischemic apoptosis by targeting Bcl-2. BDNF mitigated the pro-apoptotic effect of miR-195 in rat cardiomyocytes. These findings may

Genetic association between BDNF gene polymorphisms and phobic disorders: a case-control study among mainland Han Chinese.

PubMed

Xie, Bing; Wang, Binbin; Suo, Peisu; Kou, Changgui; Wang, Jing; Meng, Xiangfei; Cheng, Longfei; Ma, Xu; Yu, Yaqin

2011-07-01

Phobic disorders are a common group of syndromes comprising persistently recurring, irrational severe anxiety of specific objects, activities, or situations with avoidance behavior of the phobic stimulus. The present study investigated the association between whole region polymorphisms, (including the Val66Met variant), in the BDNF gene and phobic disorders among Han Chinese young adults. We conducted a case-control study to investigate the genetic association between BDNF polymorphisms and phobic disorders among mainland Chinese. One hundred and twenty young adults with phobic disorders and 267 matched controls were recruited. Three tag SNPs of BDNF were successfully genotyped by using PCR-based ligase detection reaction (PCR-LDR). We found significant differences in allele distributions of SNP rs10835210 (P<0.001) between the experimental and the control groups. In the haplotype analysis based on linkage-disequilibrium across this gene locus, we demonstrated significant association between phobic disorders and BDNF haplotype CAC (P=0.004). Association was significant after 10(4) permutation tests (P<0.001). To the best of our knowledge, this is the first study showing that the BDNF gene may play a significant role in the etiology of phobic disorders in the Han Chinese population. Copyright © 2010. Published by Elsevier B.V.

Huntingtin processing in pathogenesis of Huntington disease.

PubMed

Qin, Zheng-Hong; Gu, Zhen-Lun

2004-10-01

Huntingtons disease (HD) is caused by an expansion of the polyglutamine tract in the protein named huntingtin. The expansion of polyglutamine tract induces selective degeneration of striatal projection neurons and cortical pyramidal neurons. The bio-hallmark of HD is the formation of intranuclear inclusions and cytoplasmic aggregates in association with other cellular proteins in vulnerable neurons. Accumulation of N-terminal mutant huntingtin in HD brains is prominent. These pathological features are related to protein misfolding and impairments in protein processing and degradation in neurons. This review focused on the role of proteases in huntingtin cleavage and degradation and the contribution of altered processing of mutant huntingtin to HD pathogenesis. Copyright 2004 Acta Pharmacologica Sinica

Brain-derived neurotrophic factor (BDNF)-induced mitochondrial motility arrest and presynaptic docking contribute to BDNF-enhanced synaptic transmission.

PubMed

Su, Bo; Ji, Yun-Song; Sun, Xu-lu; Liu, Xiang-Hua; Chen, Zhe-Yu

2014-01-17

Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca(2+) buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca(2+) levels. The Ca(2+) sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca(2+) prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.

Involvement of BDNF signaling transmission from basolateral amygdala to infralimbic prefrontal cortex in conditioned taste aversion extinction.

PubMed

Xin, Jian; Ma, Ling; Zhang, Tian-Yi; Yu, Hui; Wang, Yue; Kong, Liang; Chen, Zhe-Yu

2014-05-21

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in memory extinction. However, the detailed role of BDNF in memory extinction on the basis of neural circuit has not been fully understood. Here, we aim to investigate the role of BDNF signaling circuit in mediating conditioned taste aversion (CTA) memory extinction of the rats. We found region-specific changes in BDNF gene expression during CTA extinction. CTA extinction led to increased BDNF gene expression in the basolateral amygdala (BLA) and infralimbic prefrontal cortex (IL) but not in the central amygdaloid nucleus (CeA) and hippocampus (HIP). Moreover, blocking BDNF signaling or exogenous microinjection of BDNF into the BLA or IL could disrupt or enhance CTA extinction, which suggested that BDNF signaling in the BLA and IL is necessary and sufficient for CTA extinction. Interestingly, we found that microinjection of BDNF-neutralizing antibody into the BLA could abolish the extinction training-induced BDNF mRNA level increase in the IL, but not vice versa, demonstrating that BDNF signaling is transmitted from the BLA to IL during extinction. Finally, the accelerated extinction learning by infusion of exogenous BDNF in the BLA could also be blocked by IL infusion of BDNF-neutralizing antibody rather than vice versa, indicating that the IL, but not BLA, is the primary action site of BDNF in CTA extinction. Together, these data suggest that BLA-IL circuit regulates CTA memory extinction by identifying BDNF as a key regulator. Copyright © 2014 the authors 0270-6474/14/347302-12$15.00/0.

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

PubMed

Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2015-09-01

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1.

PubMed

Yang, Jenq-Lin; Lin, Yu-Ting; Chuang, Pei-Chin; Bohr, Vilhelm A; Mattson, Mark P

2014-03-01

Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and associated learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer's, Parkinson's, and Huntington's diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in experimental models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we determined whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cyclic AMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1.

Synapsins Are Downstream Players of the BDNF-Mediated Axonal Growth.

PubMed

Marte, Antonella; Messa, Mirko; Benfenati, Fabio; Onofri, Franco

2017-01-01

Synapsins (Syns) are synaptic vesicle-associated phosphoproteins involved in neuronal development and neurotransmitter release. While Syns are implicated in the regulation of brain-derived neurotrophic factor (BDNF)-induced neurotransmitter release, their role in the BDNF developmental effects has not been fully elucidated. By using primary cortical neurons from Syn I knockout (KO) and Syn I/II/III KO mice, we studied the effects of BDNF and nerve growth factor (NGF) on axonal growth. While NGF had similar effects in all genotypes, BDNF induced significant differences in Syn KO axonal outgrowth compared to wild type (WT), an effect that was rescued by the re-expression of Syn I. Moreover, the significant increase of axonal branching induced by BDNF in WT neurons was not detectable in Syn KO neurons. The expression analysis of BDNF receptors in Syn KO neurons revealed a significant decrease of the full length TrkB receptor and an increase in the levels of the truncated TrkB.t1 isoform and p75 NTR associated with a marked reduction of the BDNF-induced MAPK/Erk activation. By using the Trk inhibitor K252a, we demonstrated that these differences in BDNF effects were dependent on a TrkB/p75 NTR imbalance. The data indicate that Syn I plays a pivotal role in the BDNF signal transduction during axonal growth.

Effects of BDNF polymorphisms on antidepressant action.

PubMed

Tsai, Shih-Jen; Hong, Chen-Jee; Liou, Ying-Jay

2010-12-01

Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidepressant treatment and since genetic factors may contribute to this inter-individual variability in antidepressant response, pharmacogenetic studies have tested the associations between genetic polymorphisms in candidate genes related to antidepressant therapeutic action. In human BDNF gene, there is a common functional polymorphism (Val66Met) in the pro-region of BDNF, which affects the intracellular trafficking of proBDNF. Because of the potentially important role of BDNF in the antidepressant mechanism, many pharmacogenetic studies have tested the association between this polymorphism and the antidepressant therapeutic response, but they have produced inconsistent results. A recent meta-analysis of eight studies, which included data from 1,115 subjects, suggested that the Val/Met carriers have increased antidepressant response in comparison to Val/Val homozygotes, particularly in the Asian population. The positive molecular heterosis effect (subjects heterozygous for a specific genetic polymorphism show a significantly greater effect) is compatible with animal studies showing that, although BDNF exerts an antidepressant effect, too much BDNF may have a detrimental effect on mood. Several recommendations are proposed for future antidepressant pharmacogenetic studies of BDNF, including the consideration of multiple polymorphisms and a haplotype approach, gene-gene interaction, a single antidepressant regimen, controlling for age and gender interactions, and pharmacogenetic

The interplay of stress and sleep impacts BDNF level.

PubMed

Giese, Maria; Unternaehrer, Eva; Brand, Serge; Calabrese, Pasquale; Holsboer-Trachsler, Edith; Eckert, Anne

2013-01-01

Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF. Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels. This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a mental disorder.

The interaction of combined effects of the BDNF and PRKCG genes and negative life events in major depressive disorder.

PubMed

Yang, Chunxia; Sun, Ning; Liu, Zhifen; Li, Xinrong; Xu, Yong; Zhang, Kerang

2016-03-30

Major depressive disorder (MDD) is a mental disorder that results from complex interplay between multiple and partially overlapping sets of susceptibility genes and environmental factors. The brain derived neurotrophic factor (BDNF) and Protein kinase C gamma type (PRKCG) are logical candidate genes in MDD. Among diverse environmental factors, negative life events have been suggested to exert a crucial impact on brain development. In the present study, we hypothesized that interactions between genetic variants in BDNF and PRKCG and negative life events may play an important role in the development of MDD. We recruited a total of 406 patients with MDD and 391 age- and gender-matched control subjects. Gene-environment interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). Under a dominant model, we observed a significant three-way interaction among BDNF rs6265, PRKCG rs3745406, and negative life events. The gene-environment combination of PRKCG rs3745406 C allele, BDNF rs6265 G allele and high level of negative life events (C-G-HN) was significantly associated with MDD (OR, 5.97; 95% CI, 2.71-13.15). To our knowledge, this is the first report of evidence that the BDNF-PRKCG interaction may modify the relationship between negative life events and MDD in the Chinese population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Astrocyte truncated-TrkB mediates BDNF antiapoptotic effect leading to neuroprotection.

PubMed

Saba, Julieta; Turati, Juan; Ramírez, Delia; Carniglia, Lila; Durand, Daniela; Lasaga, Mercedes; Caruso, Carla

2018-05-31

Astrocytes are glial cells that help maintain brain homeostasis and become reactive in neurodegenerative processes releasing both harmful and beneficial factors. We have demonstrated that brain-derived neurotrophic factor (BDNF) expression is induced by melanocortins in astrocytes but BDNF actions in astrocytes are largely unknown. We hypothesize that BDNF may prevent astrocyte death resulting in neuroprotection. We found that BDNF increased astrocyte viability, preventing apoptosis induced by serum deprivation by decreasing active caspase-3 and p53 expression. The antiapoptotic action of BDNF was abolished by ANA-12 (a specific TrkB antagonist) and by K252a (a general Trk antagonist). Astrocytes only express the BDNF receptor TrkB truncated isoform 1, TrkB-T1. BDNF induced ERK, Akt and Src (a non-receptor tyrosine kinase) activation in astrocytes. Blocking ERK and Akt pathways abolished BDNF protection in serum deprivation-induced cell death. Moreover, BDNF protected astrocytes from death by 3-nitropropionic acid (3-NP), an effect also blocked by ANA-12, K252a, and inhibitors of ERK, calcium and Src. BDNF reduced reactive oxygen species (ROS) levels induced in astrocytes by 3-NP and increased xCT expression and glutathione levels. Astrocyte conditioned media (ACM) from untreated astrocytes partially protected PC12 neurons whereas ACM from BDNF-treated astrocytes completely protected PC12 neurons from 3-NP-induced apoptosis. Both ACM from control and BDNF-treated astrocytes markedly reduced ROS levels induced by 3-NP in PC12 cells. Our results demonstrate that BDNF protects astrocytes from cell death through TrkB-T1 signaling, exerts an antioxidant action, and induces release of neuroprotective factors from astrocytes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Melatonin Promotes Brain-Derived Neurotrophic Factor (BDNF) Expression and Anti-Apoptotic Effects in Neonatal Hemolytic Hyperbilirubinemia via a Phospholipase (PLC)-Mediated Mechanism

PubMed Central

Luo, Yong; Peng, Mei; Wei, Hong

2017-01-01

Background Melatonin therapy shows positive effects on neuroprotective factor brain-derived neurotrophic factor (BDNF) expression and neuronal apoptosis in neonatal hemolytic hyperbilirubinemia. We hypothesized that melatonin promotes BDNF expression and anti-apoptotic effects in neonatal hemolytic hyperbilirubinemia through a phospholipase (PLC)-mediated mechanism. Material/Methods A phenylhydrazine hydrochloride (PHZ)-induced neonatal hemolytic hyperbilirubinemia model was constructed in neonatal rats. Four experimental groups – a control group (n=30), a PHZ group (n=30), a PHZ + melatonin group (n=30), and a PHZ + melatonin+U73122 (a PLC inhibitor) group (n=30) – were constructed. Trunk blood was assayed for serum hemoglobin, hematocrit, total and direct bilirubin, BDNF, S100B, and tau protein levels. Brain tissue levels of neuronal apoptosis, BDNF expression, PLC activity, IP3 content, phospho- and total Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV) expression, and phospho- and total cAMP response element binding protein (CREB) expression were also assayed. Results PHZ-induced hemolytic hyperbilirubinemia was validated by significantly decreased serum hemoglobin and hematocrit as well as significantly increased total and direct serum bilirubin (p<0.05). Neonatal bilirubin-induced neurotoxicity was validated by significantly decreased serum BDNF, brain BDNF, and serum S100B, along with significantly increased serum tau protein (p<0.05). PHZ-induced hemolytic hyperbilirubinemia significantly decreased serum BDNF, brain BDNF, and PLC/IP3/Ca2+ pathway activation while increasing neuronal apoptosis levels (p<0.05), all of which were partially rescued by melatonin therapy (p<0.05). Pre-treatment with the PLC inhibitor U73122 largely abolished the positive effects of melatonin on PLC/IP3/Ca2+ pathway activation, downstream BDNF levels, and neuronal apoptosis (p<0.05). Conclusions Promotion of BDNF expression and anti-apoptotic effects in neonatal

Taste bud-derived BDNF maintains innervation of a subset of TrkB-expressing gustatory nerve fibers

PubMed Central

Tang, Tao; Rios-Pilier, Jennifer; Krimm, Robin

2018-01-01

Taste receptor cells transduce different types of taste stimuli and transmit this information to gustatory neurons that carry it to the brain. Taste receptor cells turn over continuously in adulthood, requiring constant new innervation from nerve fibers. Therefore, the maintenance of innervation to taste buds is an active process mediated by many factors, including brain-derived neurotrophic factor (BDNF). Specifically, 40% of taste bud innervation is lost when Bdnf is removed during adulthood. Here we speculated that not all gustatory nerve fibers express the BDNF receptor, TrkB, resulting in subsets of neurons that vary in their response to BDNF. However, it is also possible that the partial loss of innervation occurred because the Bdnf gene was not effectively removed. To test these possibilities, we first determined that not all gustatory nerve fibers express the TrkB receptor in adult mice. We then verified the efficiency of Bdnf removal specifically in taste buds of K14-CreER:Bdnf mice and found that Bdnf expression was reduced to 1%, indicating efficient Bdnf gene recombination. BDNF removal resulted in a 55% loss of TrkB-expressing nerve fibers, which was greater than the loss of P2X3-positive fibers (39%), likely because taste buds were innervated by P2X3+/TrkB− fibers that were unaffected by BDNF removal. We conclude that gustatory innervation consists of both TrkB-positive and TrkB-negative taste fibers and that BDNF is specifically important for maintaining TrkB-positive innervation to taste buds. In addition, although taste bud size was not affected by inducible Bdnf removal, the expression of the γ subunit of the ENaC channel was reduced. So, BDNF may regulate expression of some molecular components of taste transduction pathways. PMID:28600222

Taste bud-derived BDNF maintains innervation of a subset of TrkB-expressing gustatory nerve fibers.

PubMed

Tang, Tao; Rios-Pilier, Jennifer; Krimm, Robin

2017-07-01

Taste receptor cells transduce different types of taste stimuli and transmit this information to gustatory neurons that carry it to the brain. Taste receptor cells turn over continuously in adulthood, requiring constant new innervation from nerve fibers. Therefore, the maintenance of innervation to taste buds is an active process mediated by many factors, including brain-derived neurotrophic factor (BDNF). Specifically, 40% of taste bud innervation is lost when Bdnf is removed during adulthood. Here we speculated that not all gustatory nerve fibers express the BDNF receptor, TrkB, resulting in subsets of neurons that vary in their response to BDNF. However, it is also possible that the partial loss of innervation occurred because the Bdnf gene was not effectively removed. To test these possibilities, we first determined that not all gustatory nerve fibers express the TrkB receptor in adult mice. We then verified the efficiency of Bdnf removal specifically in taste buds of K14-CreER:Bdnf mice and found that Bdnf expression was reduced to 1%, indicating efficient Bdnf gene recombination. BDNF removal resulted in a 55% loss of TrkB-expressing nerve fibers, which was greater than the loss of P2X3-positive fibers (39%), likely because taste buds were innervated by P2X3+/TrkB- fibers that were unaffected by BDNF removal. We conclude that gustatory innervation consists of both TrkB-positive and TrkB-negative taste fibers and that BDNF is specifically important for maintaining TrkB-positive innervation to taste buds. In addition, although taste bud size was not affected by inducible Bdnf removal, the expression of the γ subunit of the ENaC channel was reduced. So, BDNF may regulate expression of some molecular components of taste transduction pathways. Copyright © 2017. Published by Elsevier Inc.

Quantification Assays for Total and Polyglutamine-Expanded Huntingtin Proteins

PubMed Central

Boogaard, Ivette; Smith, Melanie; Pulli, Kristiina; Szynol, Agnieszka; Albertus, Faywell; Lamers, Marieke B. A. C.; Dijkstra, Sipke; Kordt, Daniel; Reindl, Wolfgang; Herrmann, Frank; McAllister, George; Fischer, David F.; Munoz-Sanjuan, Ignacio

2014-01-01

The expansion of a CAG trinucleotide repeat in the huntingtin gene, which produces huntingtin protein with an expanded polyglutamine tract, is the cause of Huntington's disease (HD). Recent studies have reported that RNAi suppression of polyglutamine-expanded huntingtin (mutant HTT) in HD animal models can ameliorate disease phenotypes. A key requirement for such preclinical studies, as well as eventual clinical trials, aimed to reduce mutant HTT exposure is a robust method to measure HTT protein levels in select tissues. We have developed several sensitive and selective assays that measure either total human HTT or polyglutamine-expanded human HTT proteins on the electrochemiluminescence Meso Scale Discovery detection platform with an increased dynamic range over other methods. In addition, we have developed an assay to detect endogenous mouse and rat HTT proteins in pre-clinical models of HD to monitor effects on the wild type protein of both allele selective and non-selective interventions. We demonstrate the application of these assays to measure HTT protein in several HD in vitro cellular and in vivo animal model systems as well as in HD patient biosamples. Furthermore, we used purified recombinant HTT proteins as standards to quantitate the absolute amount of HTT protein in such biosamples. PMID:24816435

Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat.

PubMed

Zhang, Yang; Gu, Fenghua; Chen, Jia; Dong, Wenxin

2010-12-17

Stress activates the hypothalamo-pituitary-adrenal (HPA) axis, regulates the expression of brain-derived neurotrophic factor (BDNF) in the brain, and mediates mood. Antidepressants alleviate stress and up-regulate BDNF gene expression. In this study, we investigated the effect of chronic unpredictable mild stress (CUMS) and the different kinds of antidepressant treatments on the HPA axis and the BDNF expression in the rat brain. Adult Wistar male rats were exposed to a six-week CUMS procedure and received different antidepressant treatments including venlafaxine, mirtazapine, and fluoxetine. Immunohistochemistry and real-time PCR were used to measure BDNF expression levels in the rat brain, and ELISAs were used to investigate the plasma corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels. CUMS significantly decreased the BDNF protein level in the DG, CA1, and CA3 of the hippocampus and increased plasma CORT level. Chronic antidepressant treatments all significantly increased BDNF protein levels in the hippocampus and the pre-frontal cortex. In addition, venlafaxine and mirtazapine inhibited the increase of plasma CORT level. These results suggested that an increase in the BDNF level in the brain could be a pivotal mechanism of various antidepressants to exert their therapeutic effects. Copyright © 2010 Elsevier B.V. All rights reserved.

Beneficial effect of fluoxetine treatment aganist psychological stress is mediated by increasing BDNF expression in selected brain areas

PubMed Central

Li, Gongying; Jing, Ping; Liu, Zhidong; Li, Zhiruo; Ma, Hongxia; Tu, Wenzhen; Zhang, Wei; Zhuo, Chuanjun

2017-01-01

SSRI antidepressant fluoxetine is widely used to treat psychological stress related disorders, however the underlying working mechanisms is not fully understood, as SSRIs can rapidly increase the extracellular serotonin levels but it normally takes weeks to reveal their therapeutic effect in the stress-related psychological disorders. Our previous study demonstrated that purely psychological stress without any physic stimuli induces a biphasic change in the expression of brain-derived neurotrophic factor (BDNF), which immediately decrease and then gradually increase after the stress; and that the latter BDNF increase in response to the psychological stress involves the activation of serotonin system. To investigate the role of BDNF in the fluoxetine treatment for stress-related psychological disorders, we examined the mRNA and protein levels of BDNF in the brain of Sprague-Dawley (SD) rats, which were pretreated with fluoxetine at 10 mg/kg or vehicle solution for 14 days, over 24 hour after an acute psychological stress exposure. In situ hybridization and immunohistochemistry were performed to detect the expression of BDNF at different time points in various brain regions after the psychological stress. We found that fluoxetine treatment completely blocked the BDNF decrease induced by the psychological stress, and also enhanced the gradual increase in the expression of BDNF in most of the brain regions except VTA after the psychological stress. The results suggest that the enhancement in BDNF levels induced by chronic fluoxetine treatment mediates the therapeutic effect against psychological stress. PMID:29050222

Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons.

PubMed

Wang, Liang; Chang, Xingya; She, Liang; Xu, Duo; Huang, Wei; Poo, Mu-ming

2015-06-03

Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activity-dependent autocrine BDNF secretion. Therefore, BDNF expressed in adult-born GCs plays a critical role in dendrite development by acting as an autocrine factor. Copyright © 2015 the authors 0270-6474/15/358384-10$15.00/0.

Brain-Derived Neurotrophic Factor (BDNF) in Traumatic Brain Injury-Related Mortality: Interrelationships Between Genetics and Acute Systemic and Central Nervous System BDNF Profiles.

PubMed

Failla, Michelle D; Conley, Yvette P; Wagner, Amy K

2016-01-01

Older adults have higher mortality rates after severe traumatic brain injury (TBI) compared to younger adults. Brain-derived neurotrophic factor (BDNF) signaling is altered in aging and is important to TBI given its role in neuronal survival/plasticity and autonomic function. Following experimental TBI, acute BDNF administration has not been efficacious. Clinically, genetic variation in BDNF (reduced signaling alleles: rs6265, Met-carriers; rs7124442, C-carriers) can be protective against acute mortality. Postacutely, these genotypes carry lower mortality risk in older adults and greater mortality risk among younger adults. Investigate BDNF levels in mortality/outcome following severe TBI in the context of age and genetic risk. Cerebrospinal fluid (CSF) and serum BDNF were assessed prospectively during the first week following severe TBI (n = 203) and in controls (n = 10). Age, BDNF genotype, and BDNF levels were assessed as mortality/outcome predictors. CSF BDNF levels tended to be higher post-TBI (P = .061) versus controls and were associated with time until death (P = .042). In contrast, serum BDNF levels were reduced post-TBI versus controls (P < .0001). Both gene * BDNF serum and gene * age interactions were mortality predictors post-TBI in the same multivariate model. CSF and serum BDNF tended to be negatively correlated post-TBI (P = .07). BDNF levels predicted mortality, in addition to gene * age interactions, suggesting levels capture additional mortality risk. Higher CSF BDNF post-TBI may be detrimental due to injury and age-related increases in pro-apoptotic BDNF target receptors. Negative CSF and serum BDNF correlations post-TBI suggest blood-brain barrier transit alterations. Understanding BDNF signaling in neuronal survival, plasticity, and autonomic function may inform treatment. © The Author(s) 2015.

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

PubMed Central

Ursini, Gianluca; Cavalleri, Tommaso; Fazio, Leonardo; Angrisano, Tiziana; Iacovelli, Luisa; Porcelli, Annamaria; Maddalena, Giancarlo; Punzi, Giovanna; Mancini, Marina; Gelao, Barbara; Romano, Raffaella; Masellis, Rita; Calabrese, Francesca; Rampino, Antonio; Taurisano, Paolo; Giorgio, Annabella Di; Keller, Simona; Tarantini, Letizia; Sinibaldi, Lorenzo; Quarto, Tiziana; Popolizio, Teresa; Caforio, Grazia; Blasi, Giuseppe; Riva, Marco A.; De Blasi, Antonio; Chiariotti, Lorenzo; Bollati, Valentina; Bertolino, Alessandro

2016-01-01

Abstract Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val66Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes. PMID:26889735

BDNF rs6265 methylation and genotype interact on risk for schizophrenia.

PubMed

Ursini, Gianluca; Cavalleri, Tommaso; Fazio, Leonardo; Angrisano, Tiziana; Iacovelli, Luisa; Porcelli, Annamaria; Maddalena, Giancarlo; Punzi, Giovanna; Mancini, Marina; Gelao, Barbara; Romano, Raffaella; Masellis, Rita; Calabrese, Francesca; Rampino, Antonio; Taurisano, Paolo; Di Giorgio, Annabella; Keller, Simona; Tarantini, Letizia; Sinibaldi, Lorenzo; Quarto, Tiziana; Popolizio, Teresa; Caforio, Grazia; Blasi, Giuseppe; Riva, Marco A; De Blasi, Antonio; Chiariotti, Lorenzo; Bollati, Valentina; Bertolino, Alessandro

2016-01-01

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

Elevation of Ser9 phosphorylation of GSK3β is required for HERV-W env-mediated BDNF signaling in human U251 cells.

PubMed

Qin, Chengchen; Li, Shan; Yan, Qiujin; Wang, Xiuling; Chen, Yatang; Zhou, Ping; Lu, Mengxin; Zhu, Fan

2016-08-03

Human endogenous retrovirus W family (HERV-W) envelope (env) is known to be associated with neurological and psychiatric disorders, such as multiple sclerosis and schizophrenia. Previous studies showed that overexpression of HERV-W env could induce brain-derived neurotrophic factor (BDNF) gene expression. In human and rat cells, BDNF-mediated signal transduction might be modulated by glycogen synthase kinase 3β (GSK3β). Both BDNF and GSK3β are schizophrenia-related genes. In this paper, we investigated whether GSK3β was involved in the HERV-W env-induced expression of BDNF. We found that HERV-W env increased phosphorylation of GSK3β at Ser9 (p-GSK3β (Ser9)) and the ratio of p-GSK3β (Ser9) to total GSK3β (p<0.05) in U251 cells. Overexpression of HERV-W env led to a 36.2% reduction in GSK3β activity compared to control (p<0.05). The levels of β-catenin, cyclin D1 and TSC2 mRNAs were upregulated (p<0.05). These data suggested that overexpression of HERV-W env might activate the GSK3β signaling pathway in U251 cells. Further, knockdown of GSK3β reduced the expression of total GSK3β, p-GSK3β (Ser9), and the ratio of p-GSK3β (Ser9) to total GSK3β by 28.6%, 50.4%, and 30.2%, respectively (p<0.05). Levels of β-catenin, cyclin D1 and TSC2 mRNAs were also reduced (p<0.05). Interestingly, GSK3β activity increased (p<0.05). Knockdown of GSK3β also decreased mRNA and protein expression of BDNF by 49.9% and 48.5% respectively (p<0.05). These results indicated that phosphorylation of GSK3β at Ser9 might be involved in HERV-W env-induced BDNF expression, and will hopefully improve our understanding of the role of HERV-W env in neurological and psychiatric diseases (schizophrenia, etc). Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Microglia promote learning-dependent synapse formation through BDNF

PubMed Central

Parkhurst, Christopher N.; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N.; Yates, John R.; Lafaille, Juan J.; Hempstead, Barbara L.; Littman, Dan R.; Gan, Wen-Biao

2014-01-01

SUMMARY Microglia are the resident macrophages of the central nervous system and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1CreER mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1CreER to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia show deficits in multiple learning tasks and a significant reduction in motor learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal TrkB phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal important physiological functions of microglia in learning and memory by promoting learning-related synapse formation through BDNF signaling. PMID:24360280

Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene

PubMed Central

Gray, Juliette; Yeo, Giles S.H.; Cox, James J.; Morton, Jenny; Adlam, Anna-Lynne R.; Keogh, Julia M.; Yanovski, Jack A.; El Gharbawy, Areeg; Han, Joan C.; Tung, Y.C. Loraine; Hodges, John R.; Raymond, F. Lucy; O’Rahilly, Stephen; Farooqi, I. Sadaf

2008-01-01

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyper-activity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior. PMID:17130481

BDNF is Associated With Age-Related Decline in Hippocampal Volume

PubMed Central

Erickson, Kirk I.; Prakash, Ruchika Shaurya; Voss, Michelle W.; Chaddock, Laura; Heo, Susie; McLaren, Molly; Pence, Brandt D.; Martin, Stephen A.; Vieira, Victoria J.; Woods, Jeffrey A.; Kramer, Arthur F.

2010-01-01

Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood. PMID:20392958

Huntingtin Acts Non Cell-Autonomously on Hippocampal Neurogenesis and Controls Anxiety-Related Behaviors in Adult Mouse

PubMed Central

Pla, Patrick; Orvoen, Sophie; Benstaali, Caroline; Dodier, Sophie; Gardier, Alain M.; David, Denis J.; Humbert, Sandrine; Saudou, Frédéric

2013-01-01

Huntington’s disease (HD) is a fatal neurodegenerative disease, characterized by motor defects and psychiatric symptoms, including mood disorders such as anxiety and depression. HD is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (HTT) protein. The development and analysis of various mouse models that express pathogenic polyQ-HTT revealed a link between mutant HTT and the development of anxio-depressive behaviors and various hippocampal neurogenesis defects. However, it is unclear whether such phenotype is linked to alteration of HTT wild-type function in adults. Here, we report the analysis of a new mouse model in which HTT is inducibly deleted from adult mature cortical and hippocampal neurons using the CreERT2/Lox system. These mice present defects in both the survival and the dendritic arborization of hippocampal newborn neurons. Our data suggest that these non-cell autonomous effects are linked to defects in both BDNF transport and release upon HTT silencing in hippocampal neurons, and in BDNF/TrkB signaling. The controlled deletion of HTT also had anxiogenic-like effects. Our results implicate endogenous wild-type HTT in adult hippocampal neurogenesis and in the control of mood disorders. PMID:24019939

Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis.

PubMed

Kambeitz, Joseph P; Bhattacharyya, Sagnik; Kambeitz-Ilankovic, Lana M; Valli, Isabel; Collier, David A; McGuire, Philip

2012-10-01

Brain derived neurotrophic factor (BDNF) is a critical component of the molecular mechanism of memory formation. Variation in the BDNF gene, particularly the rs6265 (val(66)met) single nucleotide polymorphism (SNP), has been linked to variability in human memory performance and to both the structure and physiological response of the hippocampus, which plays a central role in memory processing. However, these effects have not been consistently reported, which may reflect the modest size of the samples studied to date. Employing a meta-analytic approach, we examined the effect of the BDNF val(66)met polymorphism on human memory (5922 subjects) and hippocampal structure (2985 subjects) and physiology (362 subjects). Our results suggest that variations in the rs6265 SNP of the BDNF gene have a significant effect on memory performance, and on both the structure and physiology of the hippocampus, with carriers of the met allele being adversely affected. These results underscore the role of BDNF in moderating variability between individuals in human memory performance and in mediating some of the neurocognitive impairments underlying neuropsychiatric disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

microRNA-206 in Rat Medial Prefrontal Cortex Regulates BDNF Expression and Alcohol Drinking

PubMed Central

Barbier, Estelle; Flanigan, Meghan; Solomon, Matthew; Pincus, Alexandra; Pilling, Andrew; Sun, Hui; Schank, Jesse R.; King, Courtney; Heilig, Markus

2014-01-01

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3′-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3′-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3′-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action. PMID:24672003

microRNA-206 in rat medial prefrontal cortex regulates BDNF expression and alcohol drinking.

PubMed

Tapocik, Jenica D; Barbier, Estelle; Flanigan, Meghan; Solomon, Matthew; Pincus, Alexandra; Pilling, Andrew; Sun, Hui; Schank, Jesse R; King, Courtney; Heilig, Markus

2014-03-26

Escalation of voluntary alcohol consumption is a hallmark of alcoholism, but its neural substrates remain unknown. In rats, escalation occurs following prolonged exposure to cycles of alcohol intoxication, and is associated with persistent, wide-ranging changes in gene expression within the medial prefrontal cortex (mPFC). Here, we examined whether induction of microRNA (miR) 206 in mPFC contributes to escalated alcohol consumption. Following up on a microarray screen, quantitative real-time reverse transcription PCR (qPCR) confirmed that a history of dependence results in persistent (>3weeks) up-regulation of miR-206 expression in the mPFC, but not in the ventral tegmental area, amygdala, or nucleus accumbens. Viral-mediated overexpression of miR-206 in the mPFC of nondependent rats reproduced the escalation of alcohol self-administration seen following a history of dependence and significantly inhibited BDNF expression. Bioinformatic analysis identified three conserved target sites for miR-206 in the 3'-UTR of the rat BDNF transcript. Accordingly, BDNF was downregulated in post-dependent rats on microarray analysis, and this was confirmed by qPCR. In vitro, BDNF expression was repressed by miR-206 but not miR-9 in a 3'-UTR reporter assay, confirming BDNF as a functional target of miR-206. Mutation analysis showed that repression was dependent on the presence of all three miR-206 target sites in the BDNF 3'-UTR. Inhibition of miR-206 expression in differentiated rat cortical primary neurons significantly increased secreted levels of BDNF. In conclusion, recruitment of miR-206 in the mPFC contributes to escalated alcohol consumption following a history of dependence, with BDNF as a possible mediator of its action.

Cloning, expression analysis, and chromosomal localization of HIP1R, an isolog of huntingtin interacting protein (HIP1).

PubMed

Seki, N; Muramatsu, M; Sugano, S; Suzuki, Y; Nakagawara, A; Ohhira, M; Hayashi, A; Hori, T; Saito, T

1998-01-01

Huntington disease (HD) is an inherited neurodegenerative disorder which is associated with CAG expansion in the coding region of the gene for huntingtin protein. Recently, a huntingtin interacting protein, HIP1, was isolated by the yeast two-hybrid system. Here we report the isolation of a cDNA clone for HIP1R (huntingtin interacting protein-1 related), which encodes a predicted protein product sharing a striking homology with HIP1. RT-PCR analysis showed that the messenger RNA was ubiquitously expressed in various human tissues. Based on PCR-assisted analysis of a radiation hybrid panel and fluorescence in situ hybridization, HIP1R was localized to the q24 region of chromosome 12.

Are BDNF and glucocorticoid activities calibrated?

PubMed Central

Jeanneteau, Freddy; Chao, Moses V.

2012-01-01

One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by enhancing survival, synapse formation and synaptic plasticity. Implementation of ‘BDNF therapies’, however, faces numerous methodological and pharmacokinetic issues. Identifying BDNF mimetics that activate the BDNF receptor or downstream targets of BDNF signaling represent an alternative approach. One mechanism that shows great promise is to study the interplay of BDNF and glucocorticoid hormones, a major class of natural steroid secreted during stress reactions and in synchrony with circadian rhythms. While small amounts of glucocorticoids support normal brain function, excess stimulation by these steroid hormones precipitate stress-related affective disorders. To date, however, because of the paucity of knowledge of underlying cellular mechanisms, deleterious effects of glucocorticoids are not prevented following extreme stress. In the present review, we will discuss the complementary roles share by BDNF and glucocorticoids in synaptic plasticity, and delineate possible signaling mechanisms mediating these effects. PMID:23022538

Spirulina non-protein components induce BDNF gene transcription via HO-1 activity in C6 glioma cells.

PubMed

Morita, Kyoji; Itoh, Mari; Nishibori, Naoyoshi; Her, Song; Lee, Mi-Sook

2015-01-01

Blue-green algae are known to contain biologically active proteins and non-protein substances and considered as useful materials for manufacturing the nutritional supplements. Particularly, Spirulina has been reported to contain a variety of antioxidants, such as flavonoids, carotenoids, and vitamin C, thereby exerting their protective effects against the oxidative damage to the cells. In addition to their antioxidant actions, polyphenolic compounds have been speculated to cause the protection of neuronal cells and the recovery of neurologic function in the brain through the production of brain-derived neurotrophic factor (BDNF) in glial cells. Then, the protein-deprived extract was prepared by removing the most part of protein components from aqueous extract of Spirulina platensis, and the effect of this extract on BDNF gene transcription was examined in C6 glioma cells. Consequently, the protein-deprived extract was shown to cause the elevation of BDNF mRNA levels following the expression of heme oxygenase-1 (HO-1) in the glioma cells. Therefore, the non-protein components of S. platensis are considered to stimulate BDNF gene transcription through the HO-1 induction in glial cells, thus proposing a potential ability of the algae to indirectly modulate the brain function through the glial cell activity.

Lack of huntingtin promotes neural stem cells differentiation into glial cells while neurons expressing huntingtin with expanded polyglutamine tracts undergo cell death.

PubMed

Conforti, Paola; Camnasio, Stefano; Mutti, Cesare; Valenza, Marta; Thompson, Morgan; Fossale, Elisa; Zeitlin, Scott; MacDonald, Marcy E; Zuccato, Chiara; Cattaneo, Elena

2013-02-01

Huntington's disease (HD) is a neurodegenerative disorder that affects muscle coordination and diminishes cognitive abilities. The genetic basis of the disease is an expansion of CAG repeats in the Huntingtin (Htt) gene. Here we aimed to generate a series of mouse neural stem (NS) cell lines that carried varying numbers of CAG repeats in the mouse Htt gene (Hdh CAG knock-in NS cells) or that had Hdh null alleles (Hdh knock-out NS cells). Towards this end, Hdh CAG knock-in mouse ES cell lines that carried an Htt gene with 20, 50, 111, or 140 CAG repeats or that were Htt null were neuralized and converted into self-renewing NS cells. The resulting NS cell lines were immunopositive for the neural stem cell markers NESTIN, SOX2, and BLBP and had similar proliferative rates and cell cycle distributions. After 14 days in vitro, wild-type NS cells gave rise to cultures composed of 70% MAP2(+) neurons and 30% GFAP(+) astrocytes. In contrast, NS cells with expanded CAG repeats underwent neuronal cell death, with only 38%±15% of the MAP2(+) cells remaining at the end of the differentiation period. Cell death was verified by increased caspase 3/7 activity on day 14 of the neuronal differentiation protocol. Interestingly, Hdh knock-out NS cells treated using the same neuronal differentiation protocol showed a dramatic increase in the number of GFAP(+) cells on day 14 (61%±20% versus 24%±10% in controls), and a massive decrease of MAP2(+) neurons (30%±11% versus 64%±17% in controls). Both Hdh CAG knock-in NS cells and Hdh knock-out NS cells showed reduced levels of Bdnf mRNA during neuronal differentiation, in agreement with data obtained previously in HD mouse models and in post-mortem brain samples from HD patients. We concluded that Hdh CAG knock-in and Hdh knock-out NS cells have potential as tools for investigating the roles of normal and mutant HTT in differentiated neurons and glial cells of the brain. Copyright © 2012 Elsevier Inc. All rights reserved.

AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington's disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zuleta, Amparo; Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago; Vidal, Rene L.

2012-04-13

Highlights: Black-Right-Pointing-Pointer The contribution of ER stress to HD has not been directly addressed. Black-Right-Pointing-Pointer Expression of XBP1s using AAVs decreases Huntingtin aggregation in vivo. Black-Right-Pointing-Pointer We describe a new in vivo model of HD based on the expression of a large fragment of mHtt-RFP. -- Abstract: Huntington's disease (HD) is caused by mutations that expand a polyglutamine region in the amino-terminal domain of Huntingtin (Htt), leading to the accumulation of intracellular inclusions and progressive neurodegeneration. Recent reports indicate the engagement of endoplasmic reticulum (ER) stress responses in human HD post mortem samples and animal models of the disease. Adaptationmore » to ER stress is mediated by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates protein folding stress by controlling the expression of distinct transcription factors including X-Box binding protein 1 (XBP1). Here we targeted the expression of XBP1 on a novel viral-based model of HD. We delivered an active form of XBP1 locally into the striatum of adult mice using adeno-associated vectors (AAVs) and co-expressed this factor with a large fragment of mutant Htt as a fusion protein with RFP (Htt588{sup Q95}-mRFP) to directly visualize the accumulation of Htt inclusions in the brain. Using this approach, we observed a significant reduction in the accumulation of Htt588{sup Q95}-mRFP intracellular inclusion when XBP1 was co-expressed in the striatum. These results contrast with recent findings indicating a protective effect of XBP1 deficiency in neurodegeneration using knockout mice, and suggest a potential use of gene therapy strategies to manipulate the UPR in the context of HD.« less

Increased Steady-State Mutant Huntingtin mRNA in Huntington's Disease Brain.

PubMed

Liu, Wanzhao; Chaurette, Joanna; Pfister, Edith L; Kennington, Lori A; Chase, Kathryn O; Bullock, Jocelyn; Vonsattel, Jean Paul G; Faull, Richard L M; Macdonald, Douglas; DiFiglia, Marian; Zamore, Phillip D; Aronin, Neil

2013-01-01

Huntington's disease is caused by expansion of CAG trinucleotide repeats in the first exon of the huntingtin gene, which is essential for both development and neurogenesis. Huntington's disease is autosomal dominant. The normal allele contains 6 to 35 CAG triplets (average, 18) and the mutant, disease-causing allele contains >36 CAG triplets (average, 42). We examined 279 postmortem brain samples, including 148 HD and 131 non-HD controls. A total of 108 samples from 87 HD patients that are heterozygous at SNP rs362307, with a normal allele (18 to 27 CAG repeats) and a mutant allele (39 to 73 CAG repeats) were used to measure relative abundance of mutant and wild-type huntingtin mRNA. We used allele-specific, quantitative RT-PCR based on SNP heterozygosity to estimate the relative amount of mutant versus normal huntingtin mRNA in postmortem brain samples from patients with Huntington's disease. In the cortex and striatum, the amount of mRNA from the mutant allele exceeds that from the normal allele in 75% of patients. In the cerebellum, no significant difference between the two alleles was evident. Brain tissues from non-HD controls show no significant difference between two alleles of huntingtin mRNAs. Allelic differences were more pronounced at early neuropathological grades (grades 1 and 2) than at late grades (grades 3 and 4). More mutant HTT than normal could arise from increased transcription of mutant HTT allele, or decreased clearance of mutant HTT mRNA, or both. An implication is that equimolar silencing of both alleles would increase the mutant HTT to normal HTT ratio.

Impact of variation in the BDNF gene on social stress sensitivity and the buffering impact of positive emotions: replication and extension of a gene-environment interaction.

PubMed

van Winkel, Mark; Peeters, Frenk; van Winkel, Ruud; Kenis, Gunter; Collip, Dina; Geschwind, Nicole; Jacobs, Nele; Derom, Catherine; Thiery, Evert; van Os, Jim; Myin-Germeys, Inez; Wichers, Marieke

2014-06-01

A previous study reported that social stress sensitivity is moderated by the brain-derived-neurotrophic-factor(Val66Met) (BDNF rs6265) genotype. Additionally, positive emotions partially neutralize this moderating effect. The current study aimed to: (i) replicate in a new independent sample of subjects with residual depressive symptoms the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity, (ii) replicate the neutralizing impact of positive emotions, (iii) extend these analyses to other variations in the BDNF gene in the new independent sample and the original sample of non-depressed individuals. Previous findings were replicated in an experience sampling method (ESM) study. Negative Affect (NA) responses to social stress were stronger in "Val/Met" carriers of BDNF(Val66Met) compared to "Val/Val" carriers. Positive emotions neutralized the moderating effect of BDNF(Val66Met) genotype on social stress sensitivity in a dose-response fashion. Finally, two of four additional BDNF SNPs (rs11030101, rs2049046) showed similar moderating effects on social stress-sensitivity across both samples. The neutralizing effect of positive emotions on the moderating effects of these two additional SNPs was found in one sample. In conclusion, ESM has important advantages in gene-environment (GxE) research and may attribute to more consistent findings in future GxE research. This study shows how the impact of BDNF genetic variation on depressive symptoms may be explained by its impact on subtle daily life responses to social stress. Further, it shows that the generation of positive affect (PA) can buffer social stress sensitivity and partially undo the genetic susceptibility. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

The cryo-electron microscopy structure of huntingtin

NASA Astrophysics Data System (ADS)

Guo, Qiang; Bin Huang; Cheng, Jingdong; Seefelder, Manuel; Engler, Tatjana; Pfeifer, Günter; Oeckl, Patrick; Otto, Markus; Moser, Franziska; Maurer, Melanie; Pautsch, Alexander; Baumeister, Wolfgang; Fernández-Busnadiego, Rubén; Kochanek, Stefan

2018-03-01

Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington’s disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT. However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans) to an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The amino- and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. These data rationalize previous biochemical results and pave the way for improved understanding of the diverse cellular functions of HTT.

Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory

PubMed Central

Kim, Ana; Fagan, Anne M; Goate, Alison M; Benzinger, Tammie LS; Morris, John C; Head, Denise

2015-01-01

Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in non-human animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts. PMID:25784293

Effects of adolescent social stress and antidepressant treatment on cognitive inflexibility and Bdnf epigenetic modifications in the mPFC of adult mice.

PubMed

Xu, Hang; Wang, Jiesi; Zhang, Ke; Zhao, Mei; Ellenbroek, Bart; Shao, Feng; Wang, Weiwen

2018-02-01

Adolescent social stress (ASS) can increase susceptibility to depression in adulthood. However, the underlying psychological and neural mechanisms remain unclear. Cortically mediated cognitive dysfunctions are increasingly recognized as an independent and important risk factor of depression. Using social defeat stress, a classical animal model of depression, our previous studies found that mice subjected to this form of stress during early adolescence displayed cognitive inflexibility (CI) in adulthood. This change was accompanied by a down-regulation of Bdnf gene expression in the medial prefrontal cortex (mPFC); this gene encodes a key molecule involved in depression and antidepressant action. In the present paper, we identified epigenetic modification of Bdnf as a possible mechanism underlying the behavioral and molecular changes. ASS induced a set of depressive phenotypes, including increased social avoidance and CI, as well as reduced levels of total Bdnf and isoform IV but not isoform I or VI transcripts in the mPFC. In parallel with changes in Bdnf gene expression, previously stressed adult mice showed increased levels of dimethylation of histone H3 at lysine K9 (H3K9me2) immediately downstream of the Bdnf IV promoter. On the other hand, no differences were found in trimethylation of histone H3 at lysine K4 (H3K4me3) or in acetylation of histone H3 at lysine K9 (H3K9ac) or at K4 (H3K4ac) in the Bdnf IV promoter. Likewise, no alterations were found in DNA methylation of the Bdnf IV promoter. Additionally, treatment with the chronic antidepressant tranylcypromine reversed Bdnf epigenetic changes and related gene transcription while also reversing CI, but not social avoidance, in previously stressed adult mice. These results suggest that epigenetic changes to the Bdnf gene in the mPFC after adolescent social adversity may be involved in the regulation of cognitive dysfunction in depression and antidepressant action in adulthood. Copyright © 2017 Elsevier Ltd

BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.

PubMed

Zhao, Mingzhe; Chen, Lu; Yang, Jiarun; Han, Dong; Fang, Deyu; Qiu, Xiaohui; Yang, Xiuxian; Qiao, Zhengxue; Ma, Jingsong; Wang, Lin; Jiang, Shixiang; Song, Xuejia; Zhou, Jiawei; Zhang, Jian; Chen, Mingqi; Qi, Dong; Yang, Yanjie; Pan, Hui

2018-02-01

Depression is thought to be multifactorial in etiology, including genetic and environmental components. While a number of gene-environment interaction studies have been carried out, meta-analyses are scarce. The present meta-analysis aimed to quantify evidence on the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and stress in depression. Included were 31 peer-reviewed with a pooled total of 21060 participants published before October 2016 and literature searches were conducted using PubMed, Wolters Kluwer, Web of Science, EBSCO, Elsevier Science Direct and Baidu Scholar databases. The results indicated that the Met allele of BDNF Val66Met polymorphism significantly moderated the relationship between stress and depression (Z=2.666, p = 0.003). The results of subgroup analysis concluded that stressful life events and childhood adversity separately interacted with the Met allele of BDNF Val66Met polymorphism in depression (Z = 2.552, p = 0.005; Z = 1.775, p = 0.03). The results could be affected by errors or bias in primary studies which had small sample sizes with relatively lower statistic power. We could not estimate how strong the interaction effect between gene and environment was. We found evidence that supported the hypothesis that BDNF Val66Met polymorphism moderated the relationship between stress and depression, despite the fact that many included individual studies did not show this effect. Copyright © 2017 Elsevier B.V. All rights reserved.

BDNF gene delivery within and beyond templated agarose multi-channel guidance scaffolds enhances peripheral nerve regeneration

NASA Astrophysics Data System (ADS)

Gao, Mingyong; Lu, Paul; Lynam, Dan; Bednark, Bridget; Campana, W. Marie; Sakamoto, Jeff; Tuszynski, Mark

2016-12-01

Objective. We combined implantation of multi-channel templated agarose scaffolds with growth factor gene delivery to examine whether this combinatorial treatment can enhance peripheral axonal regeneration through long sciatic nerve gaps. Approach. 15 mm long scaffolds were templated into highly organized, strictly linear channels, mimicking the linear organization of natural nerves into fascicles of related function. Scaffolds were filled with syngeneic bone marrow stromal cells (MSCs) secreting the growth factor brain derived neurotrophic factor (BDNF), and lentiviral vectors expressing BDNF were injected into the sciatic nerve segment distal to the scaffold implantation site. Main results. Twelve weeks after injury, scaffolds supported highly linear regeneration of host axons across the 15 mm lesion gap. The incorporation of BDNF-secreting cells into scaffolds significantly increased axonal regeneration, and additional injection of viral vectors expressing BDNF into the distal segment of the transected nerve significantly enhanced axonal regeneration beyond the lesion. Significance. Combinatorial treatment with multichannel bioengineered scaffolds and distal growth factor delivery significantly improves peripheral nerve repair, rivaling the gold standard of autografts.

BDNF-TrkB signaling through Erk1/2MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids

PubMed Central

Revest, J-M; Le Roux, A; Roullot-Lacarrière, V; Kaouane, N; Vallée, M; Kasanetz, F; Rougé-Pont, F; Tronche, F; Desmedt, A; Piazza, P V

2014-01-01

Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2MAPK signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GRNesCre). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2MAPK responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2MAPK signaling pathways as one of the core effectors of stress-related effects of GC. PMID:24126929

Investigation of brain-derived neurotrophic factor (BDNF) gene expression in hypothalamus of obese rats: Modulation by omega-3 fatty acids.

PubMed

Abdel-Maksoud, Sahar M; Hassanein, Sally I; Gohar, Neveen A; Attia, Saad M M; Gad, Mohamed Z

2017-10-01

The aim of this study was investigating the effect of omega-3 fatty acids (ω-3 FAs) on brain-derived neurotrophic factor (BDNF) gene expression, using in vivo and in vitro models, to unravel the potential mechanisms of polyunsaturated fatty acids use in obesity. Twenty-nine Sprague-Dawley rats were divided into three groups; lean controls fed normal chow diet for 14 weeks, obese controls fed 60% of their diet as saturated fats for 14 weeks, and ω-3 FAs-treated rats fed 60% saturated fat diet for 14 weeks with concomitant oral administration of 400 mg/kg/day ω-3 FAs, mainly docosahexaenoic acid and EPA, from week 12 to week 14. For the in vitro experiment, hypothalamic cells from six obese rats were cultured in the presence of different concentrations of ω-3 FAs to determine its direct effect on BDNF expression. In vivo results showed that obesity has negative effect on BDNF gene expression in rat hypothalamus that was reversed by administration of ω-3 FAs. Obese rats showed hypercholesterolemia, hypertriglyceridemia, normoinsulinemia, hyperglycemia and hyperleptinemia. Treatment with ω-3 FAs showed significant decrease in serum total cholesterol and TAG. Also serum glucose level and HOMA index were decreased significantly. In vitro results demonstrated the increase in BDNF expression by ω-3 FAs in a dose-dependent manner. Obesity causes down-regulation of BDNF gene expression that can be reversed by ω-3 FAs treatment, making them an interesting treatment approach for obesity and metabolic disease.

Exploratory behavior, cortical BDNF expression, and sleep homeostasis.

PubMed

Huber, Reto; Tononi, Giulio; Cirelli, Chiara

2007-02-01

Slow-wave activity (SWA; 0.5-4.0 Hz) during non-rapid eye movement (NREM) sleep is a reliable indicator of sleep need, as it increases with the duration of prior wakefulness and decreases during sleep. However, which biologic process occurring during wakefulness is responsible for the increase of sleep SWA remains unknown. The aim of the study was to determine whether neuronal plasticity underlies the link between waking activities and the SWA response. We manipulated, in rats, the amount of exploratory activity while maintaining the total duration of waking constant. We then measured the extent to which exploration increases cortical expression of plasticity-related genes (BDNF, Arc, Homer, NGFI-A), and the SWA response once the animals were allowed to sleep. Basic neurophysiology and molecular laboratory. Male Wistar Kyoto rats (250-300 g; 2-3 month old). None. We found that, within the same animal, the amount of exploratory behavior during wakefulness could predict the extent to which BDNF was induced, as well as the extent of the homeostatic SWA response during subsequent sleep. This study suggests a direct link between the synaptic plasticity triggered by waking activities and the homeostatic sleep response and identifies BDNF as a major mediator of this link at the molecular level.

Social isolation mediated anxiety like behavior is associated with enhanced expression and regulation of BDNF in the female mouse brain.

PubMed

Kumari, Anita; Singh, Padmanabh; Baghel, Meghraj Singh; Thakur, M K

2016-05-01

Adverse early life experience is prominent risk factors for numerous psychiatric illnesses, including mood and anxiety disorders. It imposes serious long-term costs on the individual as well as health and social systems. Hence, developing therapies that prevent the long-term consequences of early life stress is of utmost importance, and necessitates a better understanding of the mechanisms by which early life stress triggers long-lasting alterations in gene expression and behavior. Post-weaning isolation rearing of rodents models the behavioral consequences of adverse early life experiences in humans and it is reported to cause anxiety like behavior which is more common in case of females. Therefore, in the present study, we have studied the impact of social isolation of young female mice for 8weeks on the anxiety like behavior and the underlying molecular mechanism. Elevated plus maze and open field test revealed that social isolation caused anxiety like behavior. BDNF, a well-known molecule implicated in the anxiety like behavior, was up-regulated both at the message and protein level in cerebral cortex by social isolation. CREB-1 and CBP, which play a crucial role in BDNF transcription, were up-regulated at mRNA level in cerebral cortex by social isolation. HDAC-2, which negatively regulates BDNF expression, was down-regulated at mRNA and protein level in cerebral cortex by social isolation. Furthermore, BDNF acts in concert with Limk-1, miRNA-132 and miRNA-134 for the regulation of structural and morphological plasticity. Social isolation resulted in up-regulation of Limk-1 mRNA and miRNA-132 expression in the cerebral cortex. MiRNA-134, which inhibits the translation of Limk-1, was decreased in cerebral cortex by social isolation. Taken together, our study suggests that social isolation mediated anxiety like behavior is associated with up-regulation of BDNF expression and concomitant increase in the expression of CBP, CREB-1, Limk-1 and miRNA-132, and decrease

Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in Dicentrarchus labrax

PubMed Central

2010-01-01

Background Stress involves alterations of brain functioning that may precipitate to mood disorders. The neurotrophin Brain Derived Neurotrophic Factor (BDNF) has recently been involved in stress-induced adaptation. BDNF is a key regulator of neuronal plasticity and adaptive processes. Regulation of BDNF is complex and may reflect not only stress-specific mechanisms but also hormonal and emotional responses. For this reason we used, as an animal model of stress, a fish whose brain organization is very similar to that of higher vertebrates, but is generally considered free of emotional reactions. Results We provide a comprehensive characterization of BDNF gene in the Dicentrarchus labrax and its transcriptional, translational and post-translational regulation following acute stress. While total BDNF mRNA levels are unchanged, BDNF transcripts 1c and 1d resulted down regulated after acute stress. Acute stress induces also a significant increase in proBDNF levels and reduction in mature BDNF suggesting altered regulation of proBDNF proteolytic processing. Notably, we provide here the first evidence that fishes possess a simplified proteolytic regulation of BDNF since the pro28Kda form, generated by the SKI-1 protease in mammals, is absent in fishes because the cleavage site has first emerged in reptilians. Finally, we show that the proBDNF/totBDNF ratio is a highly predictive novel quantitative biomarker to detect stress in fishes with sensitivity = 100%, specificity = 87%, and Negative Predictive Value = 100%. Conclusion The high predictivity of proBDNF/totBDNF ratio for stress in lower vertebrates indicates that processing of BDNF is a central mechanism in adaptation to stress and predicts that a similar regulation of pro/mature BDNF has likely been conserved throughout evolution of vertebrates from fish to man. PMID:20074340

Acute stress alters transcript expression pattern and reduces processing of proBDNF to mature BDNF in Dicentrarchus labrax.

PubMed

Tognoli, Chiara; Rossi, Federica; Di Cola, Francesco; Baj, Gabriele; Tongiorgi, Enrico; Terova, Genciana; Saroglia, Marco; Bernardini, Giovanni; Gornati, Rosalba

2010-01-14

Stress involves alterations of brain functioning that may precipitate to mood disorders. The neurotrophin Brain Derived Neurotrophic Factor (BDNF) has recently been involved in stress-induced adaptation. BDNF is a key regulator of neuronal plasticity and adaptive processes. Regulation of BDNF is complex and may reflect not only stress-specific mechanisms but also hormonal and emotional responses. For this reason we used, as an animal model of stress, a fish whose brain organization is very similar to that of higher vertebrates, but is generally considered free of emotional reactions. We provide a comprehensive characterization of BDNF gene in the Dicentrarchus labrax and its transcriptional, translational and post-translational regulation following acute stress. While total BDNF mRNA levels are unchanged, BDNF transcripts 1c and 1d resulted down regulated after acute stress. Acute stress induces also a significant increase in proBDNF levels and reduction in mature BDNF suggesting altered regulation of proBDNF proteolytic processing. Notably, we provide here the first evidence that fishes possess a simplified proteolytic regulation of BDNF since the pro28Kda form, generated by the SKI-1 protease in mammals, is absent in fishes because the cleavage site has first emerged in reptilians. Finally, we show that the proBDNF/totBDNF ratio is a highly predictive novel quantitative biomarker to detect stress in fishes with sensitivity = 100%, specificity = 87%, and Negative Predictive Value = 100%. The high predictivity of proBDNF/totBDNF ratio for stress in lower vertebrates indicates that processing of BDNF is a central mechanism in adaptation to stress and predicts that a similar regulation of pro/mature BDNF has likely been conserved throughout evolution of vertebrates from fish to man.

Daily visual stimulation in the critical period enhances multiple aspects of vision through BDNF-mediated pathways in the mouse retina

PubMed Central

Mui, Amanda M.; Yang, Victoria; Aung, Moe H.; Fu, Jieming; Adekunle, Adewumi N.; Prall, Brian C.; Sidhu, Curran S.; Park, Han na; Boatright, Jeffrey H.; Iuvone, P. Michael

2018-01-01

Visual experience during the critical period modulates visual development such that deprivation causes visual impairments while stimulation induces enhancements. This study aimed to determine whether visual stimulation in the form of daily optomotor response (OMR) testing during the mouse critical period (1) improves aspects of visual function, (2) involves retinal mechanisms and (3) is mediated by brain derived neurotrophic factor (BDNF) and dopamine (DA) signaling pathways. We tested spatial frequency thresholds in C57BL/6J mice daily from postnatal days 16 to 23 (P16 to P23) using OMR testing. Daily OMR-treated mice were compared to littermate controls that were placed in the OMR chamber without moving gratings. Contrast sensitivity thresholds, electroretinograms (ERGs), visual evoked potentials, and pattern ERGs were acquired at P21. To determine the role of BDNF signaling, a TrkB receptor antagonist (ANA-12) was systemically injected 2 hours prior to OMR testing in another cohort of mice. BDNF immunohistochemistry was performed on retina and brain sections. Retinal DA levels were measured using high-performance liquid chromatography. Daily OMR testing enhanced spatial frequency thresholds and contrast sensitivity compared to controls. OMR-treated mice also had improved rod-driven ERG oscillatory potential response times, greater BDNF immunoreactivity in the retinal ganglion cell layer, and increased retinal DA content compared to controls. VEPs and pattern ERGs were unchanged. Systemic delivery of ANA-12 attenuated OMR-induced visual enhancements. Daily OMR testing during the critical period leads to general visual function improvements accompanied by increased DA and BDNF in the retina, with this process being requisitely mediated by TrkB activation. These results suggest that novel combination therapies involving visual stimulation and using both behavioral and molecular approaches may benefit degenerative retinal diseases or amblyopia. PMID:29408880

The Role of Brain-Derived Neurotrophic Factor (BDNF) in the Development of Neurogenic Detrusor Overactivity (NDO)

PubMed Central

Frias, Bárbara; Santos, João; Morgado, Marlene; Sousa, Mónica Mendes; Gray, Susannah M.Y.; McCloskey, Karen D.; Allen, Shelley; Cruz, Francisco

2015-01-01

Neurogenic detrusor overactivity (NDO) is a well known consequence of spinal cord injury (SCI), recognizable after spinal shock, during which the bladder is areflexic. NDO emergence and maintenance depend on profound plastic changes of the spinal neuronal pathways regulating bladder function. It is well known that neurotrophins (NTs) are major regulators of such changes. NGF is the best-studied NT in the bladder and its role in NDO has already been established. Another very abundant neurotrophin is BDNF. Despite being shown that, acting at the spinal cord level, BDNF is a key mediator of bladder dysfunction and pain during cystitis, it is presently unclear if it is also important for NDO. This study aimed to clarify this issue. Results obtained pinpoint BDNF as an important regulator of NDO appearance and maintenance. Spinal BDNF expression increased in a time-dependent manner together with NDO emergence. In chronic SCI rats, BDNF sequestration improved bladder function, indicating that, at later stages, BDNF contributes NDO maintenance. During spinal shock, BDNF sequestration resulted in early development of bladder hyperactivity, accompanied by increased axonal growth of calcitonin gene-related peptide-labeled fibers in the dorsal horn. Chronic BDNF administration inhibited the emergence of NDO, together with reduction of axonal growth, suggesting that BDNF may have a crucial role in bladder function after SCI via inhibition of neuronal sprouting. These findings highlight the role of BDNF in NDO and may provide a significant contribution to create more efficient therapies to manage SCI patients. PMID:25653370

Huntingtin gene evolution in Chordata and its peculiar features in the ascidian Ciona genus

PubMed Central

Gissi, Carmela; Pesole, Graziano; Cattaneo, Elena; Tartari, Marzia

2006-01-01

Background To gain insight into the evolutionary features of the huntingtin (htt) gene in Chordata, we have sequenced and characterized the full-length htt mRNA in the ascidian Ciona intestinalis, a basal chordate emerging as new invertebrate model organism. Moreover, taking advantage of the availability of genomic and EST sequences, the htt gene structure of a number of chordate species, including the cogeneric ascidian Ciona savignyi, and the vertebrates Xenopus and Gallus was reconstructed. Results The C. intestinalis htt transcript exhibits some peculiar features, such as spliced leader trans-splicing in the 98 nt-long 5' untranslated region (UTR), an alternative splicing in the coding region, eight alternative polyadenylation sites, and no similarities of both 5' and 3'UTRs compared to homologs of the cogeneric C. savignyi. The predicted protein is 2946 amino acids long, shorter than its vertebrate homologs, and lacks the polyQ and the polyP stretches found in the the N-terminal regions of mammalian homologs. The exon-intron organization of the htt gene is almost identical among vertebrates, and significantly conserved between Ciona and vertebrates, allowing us to hypothesize an ancestral chordate gene consisting of at least 40 coding exons. Conclusion During chordate diversification, events of gain/loss, sliding, phase changes, and expansion of introns occurred in both vertebrate and ascidian lineages predominantly in the 5'-half of the htt gene, where there is also evidence of lineage-specific evolutionary dynamics in vertebrates. On the contrary, the 3'-half of the gene is highly conserved in all chordates at the level of both gene structure and protein sequence. Between the two Ciona species, a fast evolutionary rate and/or an early divergence time is suggested by the absence of significant similarity between UTRs, protein divergence comparable to that observed between mammals and fishes, and different distribution of repetitive elements. PMID:17092333

BDNF Regulates the Expression and Distribution of Vesicular Glutamate Transporters in Cultured Hippocampal Neurons

PubMed Central

Melo, Carlos V.; Silva, Carla G.; Duarte, Carlos B.

2013-01-01

BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT) 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7), indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during embryonic and neonatal

Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women.

PubMed

Unternaehrer, Eva; Meyer, Andrea Hans; Burkhardt, Susan C A; Dempster, Emma; Staehli, Simon; Theill, Nathan; Lieb, Roselind; Meinlschmidt, Gunther

2015-01-01

In adults, reporting low and high maternal care in childhood, we compared DNA methylation in two stress-associated genes (two target sequences in the oxytocin receptor gene, OXTR; one in the brain-derived neurotrophic factor gene, BDNF) in peripheral whole blood, in a cross-sectional study (University of Basel, Switzerland) during 2007-2008. We recruited 89 participants scoring < 27 (n = 47, 36 women) or > 33 (n = 42, 35 women) on the maternal care subscale of the Parental Bonding Instrument (PBI) at a previous assessment of a larger group (N = 709, range PBI maternal care = 0-36, age range = 19-66 years; median 24 years). 85 participants gave blood for DNA methylation analyses (Sequenom(R) EpiTYPER, San Diego, CA) and cell count (Sysmex PocH-100i™, Kobe, Japan). Mixed model statistical analysis showed greater DNA methylation in the low versus high maternal care group, in the BDNF target sequence [Likelihood-Ratio (1) = 4.47; p = 0.035] and in one OXTR target sequence Likelihood-Ratio (1) = 4.33; p = 0.037], but not the second OXTR target sequence [Likelihood-Ratio (1) < 0.001; p = 0.995). Mediation analyses indicated that differential blood cell count did not explain associations between low maternal care and BDNF (estimate = -0.005, 95% CI = -0.025 to 0.015; p = 0.626) or OXTR DNA methylation (estimate = -0.015, 95% CI = -0.038 to 0.008; p = 0.192). Hence, low maternal care in childhood was associated with greater DNA methylation in an OXTR and a BDNF target sequence in blood cells in adulthood. Although the study has limitations (cross-sectional, a wide age range, only three target sequences in two genes studied, small effects, uncertain relevance of changes in blood cells to gene methylation in brain), the findings may indicate components of the epiphenotype from early life stress.

The Neurotrophin-Inducible Gene Vgf Regulates Hippocampal Function and Behavior Through a BDNF-Dependent Mechanism

PubMed Central

Bozdagi, Ozlem; Rich, Erin; Tronel, Sophie; Sadahiro, Masato; Patterson, Kamara; Shapiro, Matthew L.; Alberini, Cristina M.; Huntley, George W.; Salton, Stephen R. J.

2009-01-01

VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, where it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knockout mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and by tPASTOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75NTR function-blocking antiserum, nor by prior tetanic stimulation. Although LTP was normal in slices from VGF knockout mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism, and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior. PMID:18815270

Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

PubMed Central

Munoz, Miranda J.; Kumar, Raj G.; Oh, Byung-Mo; Conley, Yvette P.; Wang, Zhensheng; Failla, Michelle D.; Wagner, Amy K.

2017-01-01

Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance. PMID:28337122

Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways

PubMed Central

Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

2015-01-01

Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses. PMID:26241953

Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

PubMed

Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

2015-01-01

Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity.

PubMed

Bates, Emily A; Victor, Martin; Jones, Adriana K; Shi, Yang; Hart, Anne C

2006-03-08

Expansion of a polyglutamine tract in the huntingtin protein causes neuronal degeneration and death in Huntington's disease patients, but the molecular mechanisms underlying polyglutamine-mediated cell death remain unclear. Previous studies suggest that expanded polyglutamine tracts alter transcription by sequestering glutamine rich transcriptional regulatory proteins, thereby perturbing their function. We tested this hypothesis in Caenorhabditis elegans neurons expressing a human huntingtin fragment with an expanded polyglutamine tract (Htn-Q150). Loss of function alleles and RNA interference (RNAi) were used to examine contributions of C. elegans cAMP response element-binding protein (CREB), CREB binding protein (CBP), and histone deacetylases (HDACs) to polyglutamine-induced neurodegeneration. Deletion of CREB (crh-1) or loss of one copy of CBP (cbp-1) enhanced polyglutamine toxicity in C. elegans neurons. Loss of function alleles and RNAi were then used to systematically reduce function of each C. elegans HDAC. Generally, knockdown of individual C. elegans HDACs enhanced Htn-Q150 toxicity, but knockdown of C. elegans hda-3 suppressed toxicity. Neuronal expression of hda-3 restored Htn-Q150 toxicity and suggested that C. elegans HDAC3 (HDA-3) acts within neurons to promote degeneration in response to Htn-Q150. Genetic epistasis experiments suggested that HDA-3 and CRH-1 (C. elegans CREB homolog) directly oppose each other in regulating transcription of genes involved in polyglutamine toxicity. hda-3 loss of function failed to suppress increased neurodegeneration in hda-1/+;Htn-Q150 animals, indicating that HDA-1 and HDA-3 have different targets with opposing effects on polyglutamine toxicity. Our results suggest that polyglutamine expansions perturb transcription of CREB/CBP targets and that specific targeting of HDACs will be useful in reducing associated neurodegeneration.

Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress

NASA Astrophysics Data System (ADS)

Leitman, Julia; Ulrich Hartl, F.; Lederkremer, Gerardo Z.

2013-11-01

In Huntington’s disease, as in other neurodegenerative diseases, it was initially thought that insoluble protein aggregates are the toxic species. However, growing evidence implicates soluble oligomeric polyglutamine-expanded huntingtin in cytotoxicity. Here we show that pathogenic huntingtin inhibits endoplasmic reticulum (ER)-associated degradation and induces ER stress before its aggregation into visible inclusions. All three branches of the unfolded protein response are activated. ER stress can be compensated by overexpression of p97/VCP, suggesting its sequestration by pathogenic huntingtin as a main cause. Stress correlates with the presence of huntingtin oligomers and is independent of continual huntingtin synthesis. Stress levels, measured in striatal neurons, are stabilized but only slowly subside on huntingtin aggregation into inclusions. Our results can be explained by the constant conversion of huntingtin monomers to toxic oligomers; large aggregates sequester the former, precluding further conversion, whereas pre-existing toxic oligomers are only gradually depleted.

BDNF — a key transducer of antidepressant effects

PubMed Central

Björkholm, Carl; Monteggia, Lisa M.

2016-01-01

How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an

The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning.

PubMed

Helm, Erin E; Matt, Kathleen S; Kirschner, Kenneth F; Pohlig, Ryan T; Kohl, Dave; Reisman, Darcy S

2017-10-01

Brain-derived neurotrophic factor (BDNF) has been directly related to exercise-enhanced motor performance in the neurologically injured animal model; however literature concerning the role of BDNF in the enhancement of motor learning in the human population is limited. Previous studies in healthy subjects have examined the relationship between intensity of an acute bout of exercise, increases in peripheral BDNF and motor learning of a simple isometric upper extremity task. The current study examined the role of high intensity exercise on upregulation of peripheral BDNF levels as well as the role of high intensity exercise in mediation of motor learning and retention of a novel locomotor task in neurologically intact adults. In addition, the impact of a single nucleotide polymorphism in the BDNF gene (Val66Met) in moderating the relationship between exercise and motor learning was explored. It was hypothesized that participation in high intensity exercise prior to practicing a novel walking task (split-belt treadmill walking) would elicit increases in peripheral BDNF as well as promote an increased rate and magnitude of within session learning and retention on a second day of exposure to the walking task. Within session learning and retention would be moderated by the presence or absence of Val66Met polymorphism. Fifty-four neurologically intact participants participated in two sessions of split-belt treadmill walking. Step length and limb phase were measured to assess learning of spatial and temporal parameters of walking. Serum BDNF was collected prior to and immediately following either high intensity exercise or 5min of quiet rest. The results demonstrated that high intensity exercise provides limited additional benefit to learning of a novel locomotor pattern in neurologically intact adults, despite increases in circulating BDNF. In addition, presence of a single nucleotide polymorphism on the BDNF gene did not moderate the magnitude of serum BDNF increases

Predicting the use of corporal punishment: Child aggression, parent religiosity, and the BDNF gene.

PubMed

Avinun, Reut; Davidov, Maayan; Mankuta, David; Knafo-Noam, Ariel

2018-03-01

Corporal punishment (CP) has been associated with deleterious child outcomes, highlighting the importance of understanding its underpinnings. Although several factors have been linked with parents' CP use, genetic influences on CP have rarely been studied, and an integrative view examining the interplay between different predictors of CP is missing. We focused on the separate and joint effects of religiosity, child aggression, parent's gender, and a valine (Val) to methionine (Met) substitution in the brain-derived neurotrophic factor (BDNF) gene. Data came from a twin sample (51% male, aged 6.5 years). We used mothers' and fathers' self-reports of CP and religiosity, and the other parent's report on child aggression. Complete data were available for 244 mothers and their 466 children, and for 217 fathers and their 409 children. The random split method was employed to examine replicability. For mothers, only the effect of religiosity appeared to replicate. For fathers, several effects predicting CP use replicated in both samples: child aggression, child sex, religiosity, and a three-way (GxExE) interaction implicating fathers' BDNF genotype, child aggression and religiosity. Religious fathers who carried the Met allele and had an aggressive child used CP more frequently; in contrast, secular fathers' CP use was not affected by their BDNF genotype or child aggression. Results were also repeated longitudinally in a subsample with age 8-9 data. Findings highlight the utility of a bio-ecological approach for studying CP use by shedding light on pertinent gene-environment interaction processes. Possible implications for intervention and public policy are discussed. © 2017 Wiley Periodicals, Inc.

The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

PubMed

Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

2017-01-01

Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

HD CAG-correlated gene expression changes support a simple dominant gain of function

PubMed Central

Jacobsen, Jessie C.; Gregory, Gillian C.; Woda, Juliana M.; Thompson, Morgan N.; Coser, Kathryn R.; Murthy, Vidya; Kohane, Isaac S.; Gusella, James F.; Seong, Ihn Sik; MacDonald, Marcy E.; Shioda, Toshi; Lee, Jong-Min

2011-01-01

Huntington's disease is initiated by the expression of a CAG repeat-encoded polyglutamine region in full-length huntingtin, with dominant effects that vary continuously with CAG size. The mechanism could involve a simple gain of function or a more complex gain of function coupled to a loss of function (e.g. dominant negative-graded loss of function). To distinguish these alternatives, we compared genome-wide gene expression changes correlated with CAG size across an allelic series of heterozygous CAG knock-in mouse embryonic stem (ES) cell lines (HdhQ20/7, HdhQ50/7, HdhQ91/7, HdhQ111/7), to genes differentially expressed between Hdhex4/5/ex4/5 huntingtin null and wild-type (HdhQ7/7) parental ES cells. The set of 73 genes whose expression varied continuously with CAG length had minimal overlap with the 754-member huntingtin-null gene set but the two were not completely unconnected. Rather, the 172 CAG length-correlated pathways and 238 huntingtin-null significant pathways clustered into 13 shared categories at the network level. A closer examination of the energy metabolism and the lipid/sterol/lipoprotein metabolism categories revealed that CAG length-correlated genes and huntingtin-null-altered genes either were different members of the same pathways or were in unique, but interconnected pathways. Thus, varying the polyglutamine size in full-length huntingtin produced gene expression changes that were distinct from, but related to, the effects of lack of huntingtin. These findings support a simple gain-of-function mechanism acting through a property of the full-length huntingtin protein and point to CAG-correlative approaches to discover its effects. Moreover, for therapeutic strategies based on huntingtin suppression, our data highlight processes that may be more sensitive to the disease trigger than to decreased huntingtin levels. PMID:21536587

Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex.

PubMed

Kazantseva, A; Gaysina, D; Kutlumbetova, Yu; Kanzafarova, R; Malykh, S; Lobaskova, M; Khusnutdinova, E

2015-01-02

Personality traits are complex phenotypes influenced by interactions of multiple genetic variants of small effect and environmental factors. It has been suggested that the brain derived neurotrophic factor gene (BDNF) is involved in personality traits. Season of birth (SOB) has also been shown to affect personality traits due to its influences on brain development during prenatal and early postnatal periods. The present study aimed to investigate the effects of BDNF on personality traits; and the modifying effects of SOB and sex on associations between BDNF and personality traits. A sample of 1018 young adults (68% women; age range 17-25years) of Caucasian origin from the Russian Federation was assessed on personality traits (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence, Self-directedness, Cooperativeness, Self-transcendence) with the Temperament and Character Inventory-125 (TCI-125). Associations between personality traits and 12 BDNF SNPs were tested using linear regression models. The present study demonstrated the effect of rs11030102 on Persistence in females only (PFDR=0.043; r(2)=1.3%). There were significant interaction effects between Val66Met (rs6265) and SOB (PFDR=0.048, r(2)=1.4%), and between rs2030323 and SOB (PFDR=0.042, r(2)=1.3%), on Harm Avoidance. Our findings provide evidence for the modifying effect of SOB on the association between BDNF and Harm Avoidance, and for the modifying effect of sex on the association between BDNF and Persistence. Copyright © 2014 Elsevier Inc. All rights reserved.

BDNF action in the brain attenuates diabetic hyperglycemia via insulin-independent inhibition of hepatic glucose production.

PubMed

Meek, Thomas H; Wisse, Brent E; Thaler, Joshua P; Guyenet, Stephan J; Matsen, Miles E; Fischer, Jonathan D; Taborsky, Gerald J; Schwartz, Michael W; Morton, Gregory J

2013-05-01

Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP.

Age-modulated association between prefrontal NAA and the BDNF gene.

PubMed

Salehi, Basira; Preuss, Nora; van der Veen, Jan Willem; Shen, Jun; Neumeister, Alexander; Drevets, Wayne C; Hodgkinson, Colin; Goldman, David; Wendland, Jens R; Singleton, Andrew; Gibbs, Jesse R; Cookson, Mark R; Hasler, Gregor

2013-07-01

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 × age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age ⩾34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.

3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons.

PubMed

Marosi, Krisztina; Kim, Sang Woo; Moehl, Keelin; Scheibye-Knudsen, Morten; Cheng, Aiwu; Cutler, Roy; Camandola, Simonetta; Mattson, Mark P

2016-12-01

During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms remain unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD + /NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain-derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-κB, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population

ERIC Educational Resources Information Center

Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen

2012-01-01

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

[Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease].

PubMed

Golimbet, V E; Volel', B A; Kopylov, F Iu; Dolzhikov, A V; Korovaitseva, G I; Kasparov, S V; Isaeva, M I

2015-01-01

In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression.

Involvement of brain-derived neurotrophic factor (BDNF) in the functional elimination of synaptic contacts at polyinnervated neuromuscular synapses during development.

PubMed

Garcia, N; Santafe, M M; Tomàs, M; Lanuza, M A; Besalduch, N; Tomàs, J

2010-05-15

We use immunohistochemistry to describe the localization of brain-derived neurotrophic factor (BDNF) and its receptors trkB and p75(NTR) in the neuromuscular synapses of postnatal rats (P6-P7) during the synapse elimination period. The receptor protein p75(NTR) is present in the nerve terminal, muscle cell and glial Schwann cell whereas BDNF and trkB proteins can be detected mainly in the pre- and postsynaptic elements. Exogenously applied BDNF (10 nM for 3 hr or 50 nM for 1 hr) increases ACh release from singly and dually innervated synapses. This effect may be specific for BDNF because the neurotrophin NT-4 (2-8 nM) does not modulate release at P6-P7. Blocking the receptors trkB and p75(NTR) (with K-252a and anti-p75-192-IgG, respectively) completely abolishes the potentiating effect of exogenous BDNF. In addition, exogenous BDNF transiently recruits functionally depressed silent terminals, and this effect seems to be mediated by trkB. Calcium ions, the L-type voltage-dependent calcium channels and protein kinase C are involved in BDNF-mediated nerve ending recruitment. Blocking experiments suggest that endogenous BDNF could operate through p75(NTR) receptors coupled to potentiate ACh release in all nerve terminals because the anti-p75-192-IgG reduces release. However, blocking the trkB receptor (K-252a) or neutralizing endogenous BDNF with the trkB-IgG fusion protein reveals a trkB-mediated release inhibition on almost mature strong endings in dual junctions. Taken together these results suggest that a BDNF-induced p75(NTR)-mediated ACh release potentiating mechanism and a BDNF-induced trkB-mediated release inhibitory mechanism may contribute to developmental synapse disconnection. (c) 2009 Wiley-Liss, Inc.

Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion.

PubMed

Mukherjee, Prerona; Whalley, Heather C; McKirdy, James W; McIntosh, Andrew M; Johnstone, Eve C; Lawrie, Stephen M; Hall, Jeremy

2011-03-31

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with affective disorders, but its role in emotion processing has not been fully established. Due to the clinically heterogeneous nature of these disorders, studying the effect of genetic variation in the BDNF gene on a common attribute such as fear processing may elucidate how the BDNF Val66Met polymorphism impacts brain function. Here we use functional magnetic resonance imaging examine the effect of the BDNF Val66Met genotype on neural activity for fear processing. Forty healthy participants performed an implicit fear task during scanning, where subjects made gender judgments from facial images with neutral or fearful emotion. Subjects were tested for facial emotion recognition post-scan. Functional connectivity was investigated using psycho-physiological interactions. Subjects were genotyped for the BDNF Val66Met polymorphism and the measures compared between genotype groups. Met carriers showed overactivation in the anterior cingulate cortex (ACC), brainstem and insula bilaterally for fear processing, along with reduced functional connectivity from the ACC to the left hippocampus, and impaired fear recognition ability. The results show that during fear processing, Met allele carriers show an increased neural response in regions previously implicated in mediating autonomic arousal. Further, the Met carriers show decreased functional connectivity with the hippocampus, which may reflect differential retrieval of emotional associations. Together, these effects show significant differences in the neural substrate for fear processing with genetic variation in BDNF. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

A brief primer on the mediational role of BDNF in the exercise-memory link.

PubMed

Loprinzi, Paul D; Frith, Emily

2018-05-02

One of the most amazing aspects of the human brain is its ability to learn information and use it to change behaviour. A key neurotrophin that influences memory function is brain-derived neurotrophic factor (BDNF). This review briefly discusses the mechanistic role that BDNF may play in facilitating learning and memory. We also describe the role of exercise on this relationship. As discussed herein, BDNF may influence memory via BDNF-induced alterations in membrane receptor expression and translocation, as well as activating several pathways (PLC-y, PI3K, ERK) that act together to facilitate cellular effects that influence synaptic plasticity. Exercise may help to facilitate BDNF expression and its downstream cellular pathways from both direct and indirect mechanisms. © 2018 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

Accommodation of structural rearrangements in the huntingtin-interacting protein 1 coiled-coil domain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilbur, Jeremy D., E-mail: jwilbur@msg.ucsf.edu; Hwang, Peter K.; Brodsky, Frances M.

2010-03-01

Variable packing interaction related to the conformational flexibility within the huntingtin-interacting protein 1 coiled coil domain. Huntingtin-interacting protein 1 (HIP1) is an important link between the actin cytoskeleton and clathrin-mediated endocytosis machinery. HIP1 has also been implicated in the pathogenesis of Huntington’s disease. The binding of HIP1 to actin is regulated through an interaction with clathrin light chain. Clathrin light chain binds to a flexible coiled-coil domain in HIP1 and induces a compact state that is refractory to actin binding. To understand the mechanism of this conformational regulation, a high-resolution crystal structure of a stable fragment from the HIP1 coiled-coilmore » domain was determined. The flexibility of the HIP1 coiled-coil region was evident from its variation from a previously determined structure of a similar region. A hydrogen-bond network and changes in coiled-coil monomer interaction suggest that the HIP1 coiled-coil domain is uniquely suited to allow conformational flexibility.« less

Ethanol-BDNF interactions: Still More Questions than Answers

PubMed Central

Davis, Margaret I.

2008-01-01

Brain Derived Neurotrophic Factor (BDNF) has emerged as a regulator of development, plasticity and, recently, addiction. Decreased neurotrophic activity may be involved in ethanol-induced neurodegeneration in the adult brain and in the etiology of alcohol-related neurodevelopmental disorders. This can occur through decreased expression of BDNF or through inability of the receptor to transduce signals in the presence of ethanol. In contrast, recent studies implicate region-specific up-regulation of BDNF and associated signaling pathways in anxiety, addiction and homeostasis after ethanol exposure. Anxiety and depression are precipitating factors for substance abuse and these disorders also involve region-specific changes in BDNF in both pathogenesis and response to pharmacotherapy. Polymorphisms in the genes coding for BDNF and its receptor TrkB are linked to affective, substance abuse and appetitive disorders and therefore may play a role in the development of alcoholism. This review summarizes historical and pre-clinical data on BDNF and TrkB as it relates to ethanol toxicity and addiction. Many unresolved questions about region-specific changes in BDNF expression and the precise role of BDNF in neuropsychiatric disorders and addiction remain to be elucidated. Resolution of these questions will require significant integration of the literature on addiction and comorbid psychiatric disorders that contribute to the development of alcoholism. PMID:18394710

Huntingtin interacting protein 1 Is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors.

PubMed

Rao, D S; Chang, J C; Kumar, P D; Mizukami, I; Smithson, G M; Bradley, S V; Parlow, A F; Ross, T S

2001-11-01

Huntingtin-interacting protein 1 (HIP1) interacts with huntingtin, the protein whose gene is mutated in Huntington's disease. In addition, a fusion between HIP1 and platelet-derived growth factor beta receptor causes chronic myelomonocytic leukemia. The HIP1 proteins, including HIP1 and HIP1-related (HIP1r), have an N-terminal polyphosphoinositide-interacting epsin N-terminal homology, domain, which is found in proteins involved in clathrin-mediated endocytosis. HIP1 and HIP1r also share a central leucine zipper and an actin binding TALIN homology domain. Here we show that HIP1, like HIP1r, colocalizes with clathrin coat components. We also show that HIP1 physically associates with clathrin and AP-2, the major components of the clathrin coat. To further understand the putative biological role(s) of HIP1, we have generated a targeted deletion of murine HIP1. HIP1(-/-) mice developed into adulthood, did not develop overt neurologic symptoms in the first year of life, and had normal peripheral blood counts. However, HIP1-deficient mice exhibited testicular degeneration with increased apoptosis of postmeiotic spermatids. Postmeiotic spermatids are the only cells of the seminiferous tubules that express HIP1. These findings indicate that HIP1 is required for differentiation, proliferation, and/or survival of spermatogenic progenitors. The association of HIP1 with clathrin coats and the requirement of HIP1 for progenitor survival suggest a role for HIP1 in the regulation of endocytosis.

Huntingtin Interacting Protein 1 Is a Clathrin Coat Binding Protein Required for Differentiation of late Spermatogenic Progenitors

PubMed Central

Rao, Dinesh S.; Chang, Jenny C.; Kumar, Priti D.; Mizukami, Ikuko; Smithson, Glennda M.; Bradley, Sarah V.; Parlow, A. F.; Ross, Theodora S.

2001-01-01

Huntingtin-interacting protein 1 (HIP1) interacts with huntingtin, the protein whose gene is mutated in Huntington's disease. In addition, a fusion between HIP1 and platelet-derived growth factor β receptor causes chronic myelomonocytic leukemia. The HIP1 proteins, including HIP1 and HIP1-related (HIP1r), have an N-terminal polyphosphoinositide-interacting epsin N-terminal homology, domain, which is found in proteins involved in clathrin-mediated endocytosis. HIP1 and HIP1r also share a central leucine zipper and an actin binding TALIN homology domain. Here we show that HIP1, like HIP1r, colocalizes with clathrin coat components. We also show that HIP1 physically associates with clathrin and AP-2, the major components of the clathrin coat. To further understand the putative biological role(s) of HIP1, we have generated a targeted deletion of murine HIP1. HIP1−/− mice developed into adulthood, did not develop overt neurologic symptoms in the first year of life, and had normal peripheral blood counts. However, HIP1-deficient mice exhibited testicular degeneration with increased apoptosis of postmeiotic spermatids. Postmeiotic spermatids are the only cells of the seminiferous tubules that express HIP1. These findings indicate that HIP1 is required for differentiation, proliferation, and/or survival of spermatogenic progenitors. The association of HIP1 with clathrin coats and the requirement of HIP1 for progenitor survival suggest a role for HIP1 in the regulation of endocytosis. PMID:11604514

BDNF is essential to promote persistence of long-term memory storage

PubMed Central

Bekinschtein, Pedro; Cammarota, Martín; Katche, Cynthia; Slipczuk, Leandro; Rossato, Janine I.; Goldin, Andrea; Izquierdo, Ivan; Medina, Jorge H.

2008-01-01

Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage. PMID:18263738

Associations between parenting behavior and anxiety in a rodent model and a clinical sample: relationship to peripheral BDNF levels

PubMed Central

Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segala, S; Salum, G A; Manfro, G G; Silveira, P P

2012-01-01

Adverse early-life environment is associated with anxiety-like behaviors and disorders. Brain-derived neurotrophic factor (BDNF) is sensitive to this environment and could be a marker of underlying brain changes. We aimed at evaluating the development of anxiety-like behaviors in a rat model of early adversity, as well as the possible association with BDNF levels. Similar associations were investigated in a sample of adolescent humans. For the rat study, Wistar rat litters were divided into: early-life stress (ELS, limited access to nesting material) and control groups. Maternal behavior was observed from days 1 to 9 of life and, as adults, rats were subjected to behavioral testing and BDNF measurements in plasma, hippocampus, amygdala and periaqueductal gray. For the human study, 129 adolescents were evaluated for anxiety symptoms and perceived parental care. Serum BDNF levels and the Val66Met polymorphism of the BDNF gene were investigated. We found that ELS dams showed more pure contact, that is, contact with low care and high control, toward pups, and their adult offspring demonstrated higher anxiety-like behaviors and plasma BDNF. Also the pure contact correlated positively with adult peripheral BDNF. Similarly in humans, there was a positive correlation between maternal overprotection and serum BDNF only in Met carriers. We also found negative correlations between maternal warmth and separation anxiety, social phobia and school phobia. Finally, our translational approach revealed that ELS, mediated through variations in maternal care, is associated with anxiety in both rats and humans and increased peripheral BDNF may be marking these phenomena. PMID:23168995

Identification of a functionally distinct truncated BDNF mRNA splice variant and protein in Trachemys scripta elegans.

PubMed

Ambigapathy, Ganesh; Zheng, Zhaoqing; Li, Wei; Keifer, Joyce

2013-01-01

Brain-derived neurotrophic factor (BDNF) has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF) are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein.

Identification of a Functionally Distinct Truncated BDNF mRNA Splice Variant and Protein in Trachemys scripta elegans

PubMed Central

Ambigapathy, Ganesh; Zheng, Zhaoqing; Li, Wei; Keifer, Joyce

2013-01-01

Brain-derived neurotrophic factor (BDNF) has a diverse functional role and complex pattern of gene expression. Alternative splicing of mRNA transcripts leads to further diversity of mRNAs and protein isoforms. Here, we describe the regulation of BDNF mRNA transcripts in an in vitro model of eyeblink classical conditioning and a unique transcript that forms a functionally distinct truncated BDNF protein isoform. Nine different mRNA transcripts from the BDNF gene of the pond turtle Trachemys scripta elegans (tBDNF) are selectively regulated during classical conditioning: exon I mRNA transcripts show no change, exon II transcripts are downregulated, while exon III transcripts are upregulated. One unique transcript that codes from exon II, tBDNF2a, contains a 40 base pair deletion in the protein coding exon that generates a truncated tBDNF protein. The truncated transcript and protein are expressed in the naïve untrained state and are fully repressed during conditioning when full-length mature tBDNF is expressed, thereby having an alternate pattern of expression in conditioning. Truncated BDNF is not restricted to turtles as a truncated mRNA splice variant has been described for the human BDNF gene. Further studies are required to determine the ubiquity of truncated BDNF alternative splice variants across species and the mechanisms of regulation and function of this newly recognized BDNF protein. PMID:23825634

Age-Dependent Deficits in Fear Learning in Heterozygous BDNF Knock-Out Mice

ERIC Educational Resources Information Center

Endres, Thomas; Lessmann, Volkmar

2012-01-01

Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF…

Class I histone deacetylase-mediated repression of the proximal promoter of the activity-regulated cytoskeleton-associated protein gene regulates its response to brain-derived neurotrophic factor.

PubMed

Fukuchi, Mamoru; Nakashima, Fukumi; Tabuchi, Akiko; Shimotori, Masataka; Tatsumi, Saori; Okuno, Hiroyuki; Bito, Haruhiko; Tsuda, Masaaki

2015-03-13

We examined the transcriptional regulation of the activity-regulated cytoskeleton-associated protein gene (Arc), focusing on BDNF-induced Arc expression in cultured rat cortical cells. Although the synaptic activity-responsive element (SARE), located -7 kbp upstream of the Arc transcription start site, responded to NMDA, BDNF, or FGF2, the proximal region of the promoter (Arc/-1679) was activated by BDNF or FGF2, but not by NMDA, suggesting the presence of at least two distinct Arc promoter regions, distal and proximal, that respond to extracellular stimuli. Specificity protein 4 (SP4) and early growth response 1 (EGR1) controlled Arc/-1679 transcriptional activity via the region encompassing -169 to -37 of the Arc promoter. We found that trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, significantly enhanced the inductive effects of BDNF or FGF2, but not those of NMDA on Arc expression. Inhibitors of class I/IIb HDACs, SAHA, and class I HDACs, MS-275, but not of class II HDACs, MC1568, enhanced BDNF-induced Arc expression. The enhancing effect of TSA was mediated by the region from -1027 to -1000 bp, to which serum response factor (SRF) and HDAC1 bound. The binding of HDAC1 to this region was reduced by TSA. Thus, Arc expression was suppressed by class I HDAC-mediated mechanisms via chromatin modification of the proximal promoter whereas the inhibition of HDAC allowed Arc expression to be markedly enhanced in response to BDNF or FGF2. These results contribute to our understanding of the physiological role of Arc expression in neuronal functions such as memory consolidation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Minimal traumatic brain injury causes persistent changes in DNA methylation at BDNF gene promoters in rat amygdala: A possible role in anxiety-like behaviors.

PubMed

Sagarkar, Sneha; Bhamburkar, Tanmayi; Shelkar, Gajanan; Choudhary, Amit; Kokare, Dadasaheb M; Sakharkar, Amul J

2017-10-01

Minimal traumatic brain injury (MTBI) often transforms into chronic neuropsychiatric conditions including anxiety, the underlying mechanisms of which are largely unknown. In the present study, we employed the closed-head injury paradigm to induce MTBI in rats and examined whether DNA methylation can explain long-term changes in the expression of the brain-derived neurotrophic factor (BDNF) in the amygdala as well as trauma-induced anxiety-like behaviors. The MTBI caused anxiety-like behaviors and altered the expression of DNA methyltransferase (DNMT) isoforms (DNMT1, DNMT3a, and DNMT3b) and factors involved in DNA demethylation such as the growth arrest and DNA damage 45 (GADD45a and GADD45b). After 30days of MTBI, the over-expression of DNMT3a and DNMT3b corresponded to heightened DNMT activity, whereas the mRNA levels of GADD45a and GADD45b were declined. The methylated cytosine levels at the BDNF promoters (Ip, IVp and IXp) were increased in the amygdala of the trauma-induced animals; these coincided negatively with the mRNA levels of exon IV and IXa, but not of exon I. Interestingly, treatment with 5-azacytidine, a pan DNMT inhibitor, normalized the MTBI-induced DNMT activity and DNA hypermethylation at exon IVp and IXp. Furthermore, 5-azacytidine also corrected the deficits in the expression of exons IV and IXa and reduced the anxiety-like behaviors. These results suggest that the DNMT-mediated DNA methylation at the BDNF IVp and IXp might be involved in the regulation of BDNF gene expression in the amygdala. Further, it could also be related to MTBI-induced anxiety-like behaviors via the regulation of synaptic plasticity. Copyright © 2017 Elsevier Inc. All rights reserved.

BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals

PubMed Central

Chen, Wenling; Walwyn, Wendy; Ennes, Helena S.; Kim, Hyeyoung; McRoberts, James A.; Marvizón, Juan Carlos G.

2014-01-01

NMDA receptors in primary afferent terminals can contribute to hyperalgesia by increasing neurotransmitter release. In rats and mice, we found that the ability of intrathecal NMDA to induce neurokinin 1 receptor (NK1R) internalization (a measure of substance P release) required a previous injection of BDNF. Selective knock-down of NMDA receptors in primary afferents decreased NMDA-induced NK1R internalization, confirming the presynaptic location of these receptors. The effect of BDNF was mediated by tropomyosin-related kinase B (trkB) receptors and not p75 neurotrophin receptors (p75NTR), because it was not produced by proBDNF and was inhibited by the trkB antagonist ANA-12 but not by the p75NTR inhibitor TAT-Pep5. These effects are probably mediated through the truncated form of the trkB receptor as there is little expression of full-length trkB in dorsal root ganglion (DRG) neurons. Src family kinase inhibitors blocked the effect of BDNF, suggesting that trkB receptors promote the activation of these NMDA receptors by Src family kinase phosphorylation. Western blots of cultured DRG neurons revealed that BDNF increased Tyr1472 phosphorylation of the NR2B subunit of the NMDA receptor, known to have a potentiating effect. Patch-clamp recordings showed that BDNF, but not proBDNF, increased NMDA receptor currents in cultured DRG neurons. NMDA-induced NK1R internalization was also enabled in a neuropathic pain model or by activating dorsal horn microglia with lipopolysaccharide. These effects were decreased by a BDNF scavenger, a trkB receptor antagonist and an Src family kinase inhibitor, indicating that BDNF released by microglia potentiates NMDA receptors in primary afferents during neuropathic pain. PMID:24611998

DREAM regulates BDNF-dependent spinal sensitization

PubMed Central

2010-01-01

Background The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca2+- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia. Results L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents. Peripheral inflammation produced enhancement of spinal reflexes and increased expression of BDNF in wild type but not in DREAM transgenic mice. The enhancement of the spinal reflexes was reproduced in vitro by persistent electrical stimulation of C-fibers in wild type but not in transgenic mice. Exposure to exogenous BDNF produced a long-term enhancement of dorsal root-ventral root responses in transgenic mice. Conclusions Our results indicate that endogenous BDNF is involved in spinal sensitization following inflammation and that blockade of BDNF induction in DREAM transgenic mice underlies the failure to develop spinal sensitization. PMID:21167062

ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line

PubMed Central

Liang, Yideng; Jiang, Haibing; Ratovitski, Tamara; Jie, Chunfa; Nakamura, Masayuki; Hirschhorn, Ricky R.; Wang, Xiaofang; Smith, Wanli W.; Hai, Tsonwin; Poirier, Michelle A.; Ross, Christopher A.

2009-01-01

Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine expansion near the N-terminus of huntingtin. The mechanisms of polyglutamine neurotoxicity, and cellular responses are not fully understood. We have studied gene expression profiles by cDNA array using an inducible PC12 cell model expressing an N-terminal huntingtin fragment with expanded polyglutamine (Htt-N63-148Q). Mutant huntingtin Htt-N63 induced cell death and increased the mRNA and protein levels of activating transcription factor 3 (ATF3). Mutant Htt-N63 also significantly enhanced ATF3 transcriptional activity by a promoter-based reporter assay. Overexpression of ATF3 protects against mutant Htt-N63 toxicity and knocking down ATF3 expression reduced Htt-N63 toxicity in a stable PC12 cell line. These results indicated that ATF3 plays a critical role in toxicity induced by mutant Htt-N63 and may lead to a useful therapeutic target. PMID:19559011

BDNF and TNF-α polymorphisms in memory.

PubMed

Yogeetha, B S; Haupt, L M; McKenzie, K; Sutherland, H G; Okolicsyani, R K; Lea, R A; Maher, B H; Chan, R C K; Shum, D H K; Griffiths, L R

2013-09-01

Here, we investigate the genetic basis of human memory in healthy individuals and the potential role of two polymorphisms, previously implicated in memory function. We have explored aspects of retrospective and prospective memory including semantic, short term, working and long-term memory in conjunction with brain derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-α). The memory scores for healthy individuals in the population were obtained for each memory type and the population was genotyped via restriction fragment length polymorphism for the BDNF rs6265 (Val66Met) SNP and via pyrosequencing for the TNF-α rs113325588 SNP. Using univariate ANOVA, a significant association of the BDNF polymorphism with visual and spatial memory retention and a significant association of the TNF-α polymorphism was observed with spatial memory retention. In addition, a significant interactive effect between BDNF and TNF-α polymorphisms was observed in spatial memory retention. In practice visual memory involves spatial information and the two memory systems work together, however our data demonstrate that individuals with the Val/Val BDNF genotype have poorer visual memory but higher spatial memory retention, indicating a level of interaction between TNF-α and BDNF in spatial memory retention. This is the first study to use genetic analysis to determine the interaction between BDNF and TNF-α in relation to memory in normal adults and provides important information regarding the effect of genetic determinants and gene interactions on human memory.

Serum Brain-Derived Neurotrophic Factor is Related to Platelet Reactivity but not to Genetic Polymorphisms within BDNF Encoding Gene in Patients with Type 2 Diabetes.

PubMed

Eyileten, Ceren; Zaremba, Małgorzata; Janicki, Piotr K; Rosiak, Marek; Cudna, Agnieszka; Kapłon-Cieślicka, Agnieszka; Opolski, Grzegorz; Filipiak, Krzysztof J; Kosior, Dariusz A; Mirowska-Guzel, Dagmara; Postula, Marek

2016-01-07

The aim of this study was to investigate the association between serum concentrations of the brain-derived neurotrophic factor (BDNF), platelet reactivity and inflammatory markers, as well as its association with BDNF encoding gene variants in type 2 diabetic patients (T2DM) during acetylsalicylic acid (ASA) therapy. This retrospective, open-label study enrolled 91 patients. Serum BDNF, genotype variants, hematological, biochemical, and inflammatory markers were measured. Blood samples were taken in the morning 2-3 h after the last ASA dose. The BDNF genotypes for selected variants were analyzed by use of the iPLEX Sequenom assay. In multivariate linear regression analysis, CADP-CT >74 sec (p<0.001) and sP-selectin concentration (p=0.03) were predictive of high serum BDNF. In multivariate logistic regression analysis, CADP-CT >74 sec (p=0.02) and IL-6 concentration (p=0.03) were risk factors for serum BDNF above the median. Non-significant differences were observed between intronic SNP rs925946, missense SNP rs6265, and intronic SNP rs4923463 allelic groups and BDNF concentrations in the investigated cohort. Chronic inflammatory condition and enhanced immune system are associated with the production of BDNF, which may be why the serum BDNF level in T2DM patients with high platelet reactivity was higher compared to subjects with normal platelet reactivity in this study.

Identification and classification of genes regulated by phosphatidylinositol 3-kinase- and TRKB-mediated signalling pathways during neuronal differentiation in two subtypes of the human neuroblastoma cell line SH-SY5Y.

PubMed

Nishida, Yuichiro; Adati, Naoki; Ozawa, Ritsuko; Maeda, Aasami; Sakaki, Yoshiyuki; Takeda, Tadayuki

2008-10-28

SH-SY5Y cells exhibit a neuronal phenotype when treated with all-trans retinoic acid (RA), but the molecular mechanism of activation in the signalling pathway mediated by phosphatidylinositol 3-kinase (PI3K) is unclear. To investigate this mechanism, we compared the gene expression profiles in SK-N-SH cells and two subtypes of SH-SY5Y cells (SH-SY5Y-A and SH-SY5Y-E), each of which show a different phenotype during RA-mediated differentiation. SH-SY5Y-A cells differentiated in the presence of RA, whereas RA-treated SH-SY5Y-E cells required additional treatment with brain-derived neurotrophic factor (BDNF) for full differentiation. After exposing cells to a PI3K inhibitor, LY294002, we identified 386 genes and categorised these genes into two clusters dependent on the PI3K signalling pathway during RA-mediated differentiation in SH-SY5Y-A cells. Transcriptional regulation of the gene cluster, including 158 neural genes, was greatly reduced in SK-N-SH cells and partially impaired in SH-SY5Y-E cells, which is consistent with a defect in the neuronal phenotype of these cells. Additional stimulation with BDNF induced a set of neural genes that were down-regulated in RA-treated SH-SY5Y-E cells but were abundant in differentiated SH-SY5Y-A cells. We identified gene clusters controlled by PI3K- and TRKB-mediated signalling pathways during the differentiation of two subtypes of SH-SY5Y cells. The TRKB-mediated bypass pathway compensates for impaired neural function generated by defects in several signalling pathways, including PI3K in SH-SY5Y-E cells. Our expression profiling data will be useful for further elucidation of the signal transduction-transcriptional network involving PI3K or TRKB.

Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence.

PubMed

Wojnar, Marcin; Brower, Kirk J; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

2009-04-01

The purpose of this study was to examine relationships between genetic markers of central serotonin (5-HT) and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger. The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.

Association between Val66Met Brain-Derived Neurotrophic Factor (BDNF) Gene Polymorphism and Post-Treatment Relapse in Alcohol Dependence

PubMed Central

Wojnar, Marcin; Brower, Kirk J.; Strobbe, Stephen; Ilgen, Mark; Matsumoto, Halina; Nowosad, Izabela; Sliwerska, Elzbieta; Burmeister, Margit

2009-01-01

Background The purpose of this study was to examine relationships between genetic markers of central serotonin and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. Methods The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately one year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. Results Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse (OR = 2.62; p = 0.019), and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (HR = 4.93, p = 0.001) were even stronger. Conclusions The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies

BDNF in schizophrenia, depression and corresponding animal models.

PubMed

Angelucci, F; Brenè, S; Mathé, A A

2005-04-01

Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.

Brain-Derived Neurotrophic Factor in TBI-related mortality: Interrelationships between Genetics and Acute Systemic and CNS BDNF Profiles

PubMed Central

Failla, Michelle D.; Conley, Yvette P.; Wagner, Amy K.

2015-01-01

Background Older adults have higher mortality rates after severe traumatic brain injury (TBI) compared to younger adults. Brain derived neurotrophic factor (BDNF) signaling is altered in aging and is important to TBI given its role in neuronal survival/plasticity and autonomic function. Following experimental TBI, acute BDNF administration has not been efficacious. Clinically, genetic variation in BDNF (reduced signaling alleles: rs6265, Met-carriers; rs7124442, C-carriers) were protective in acute mortality. Post-acutely, these genotypes carried lower mortality risk in older adults, and greater mortality risk among younger adults. Objective Investigate BDNF levels in mortality/outcome following severe TBI in the context of age and genetic risk. Methods CSF and serum BDNF were assessed prospectively during the first week following severe TBI (n=203), and in controls (n=10). Age, BDNF genotype, and BDNF levels were assessed as mortality/outcome predictors. Results CSF BDNF levels tended to be higher post-TBI (p=0.061) versus controls and were associated with time until death (p=0.042). In contrast, serum BDNF levels were reduced post-TBI versus controls (p<0.0001). Both gene*BDNF serum and gene*age interactions were mortality predictors post-TBI in the same multivariate model. CSF and serum BDNF tended to be negatively correlated post-TBI (p=0.07). Conclusions BDNF levels predicted mortality, in addition to gene*age interactions, suggesting levels capture additional mortality risk. Higher CSF BDNF post-TBI may be detrimental due to injury and age-related increases in pro-apoptotic BDNF target receptors. Negative CSF and serum BDNF correlations post-TBI suggest blood-brain barrier transit alterations. Understanding BDNF signaling in neuronal survival, plasticity, and autonomic function may inform treatment. PMID:25979196

The effect of enriched environment across ages: A study of anhedonia and BDNF gene induction.

PubMed

Dong, B E; Xue, Y; Sakata, K

2018-05-02

Enriched environment treatment (EET) is a potential intervention for depression by inducing brain-derived neurotrophic factor (BDNF). However, its age dependency remains unclear. We recently found that EET during early-life development (ED) was effective in increasing exploratory activity and anti-despair behavior, particularly in promoter IV-driven BDNF deficient mice (KIV), with the largest BDNF protein induction in the hippocampus and frontal cortex. Here, we further determined age dependency of EET effects on anhedonia and promoter-specific BDNF transcription, by using the sucrose preference test and qRT-PCR. Wild-type (WT) and KIV mice received 2 months of EET during ED, young-adulthood and old-adulthood (0-2, 2-4 and 12-14 months, respectively). All KIV groups showed reduced sucrose preference, which EET equally reversed regardless of age. EET increased hippocampal BDNF mRNA levels for all ages and genotypes, but increased frontal cortex BDNF mRNA levels only in ED KIV and old WT mice. Transcription by promoters I and IV was age-dependent in the hippocampus of WT mice: more effective induction of exon IV or I during ED or old-adulthood, respectively. Transcription by almost all 9 promoters was age-specific in the frontal cortex, mostly observed in ED KIV mice. After discontinuance of EET, the EET effects on anti-anhedonia and BDNF transcription in both regions persisted only in ED KIV mice. These results suggested that EET was equally effective in reversing anhedonia and inducing hippocampal BDNF transcription, but was more effective during ED in inducing frontal cortex BDNF transcription and for lasting anti-anhedonic and BDNF effects particularly in promoter IV-BDNF deficiency. © 2018 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

BACHD rats expressing full-length mutant huntingtin exhibit differences in social behavior compared to wild-type littermates

PubMed Central

Manfré, Giuseppe; Novati, Arianna; Faccini, Ilaria; Rossetti, Andrea C.; Bosch, Kari; Molteni, Raffaella; Riva, Marco A.; Van der Harst, Johanneke E.; Homberg, Judith R.

2018-01-01

Background Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype. Objective This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT) rats at different ages, using two different measures of sociability. Methods Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT-PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF) to the observed behavioral alterations. Results In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype-effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats

MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning-dependent alternative splicing of the BDNF gene in Turtle

PubMed Central

Zheng, Zhaoqing; Ambigapathy, Ganesh; Keifer, Joyce

2017-01-01

MECP2 mutations underlying Rett syndrome cause widespread misregulation of gene expression. Functions for MeCP2 other than transcriptional are not well understood. In an ex vivo brain preparation from the pond turtle Trachemys scripta elegans, an intraexonic splicing event in the brain-derived neurotrophic factor (BDNF) gene generates a truncated mRNA transcript in naïve brain that is suppressed upon classical conditioning. MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naïve but dissociate during conditioning; the dissociation correlating with decreased DNA methylation. Surprisingly, conditioning results in new occupancy of BDNF chromatin by DNA insulator protein CCCTC-binding factor (CTCF), which is associated with suppression of splicing in conditioning. Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing. DOI: http://dx.doi.org/10.7554/eLife.25384.001 PMID:28594324

The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice.

PubMed

Uchida, Kenzo; Nakajima, Hideaki; Hirai, Takayuki; Yayama, Takafumi; Chen, Kebing; Guerrero, Alexander Rodriguez; Johnson, William Eustace; Baba, Hisatoshi

2012-12-15

The twy/twy mouse undergoes spontaneous chronic mechanical compression of the spinal cord; this in vivo model system was used to examine the effects of retrograde adenovirus (adenoviral vector [AdV])-mediated brain-derived neurotrophic factor (BDNF) gene delivery to spinal neural cells. To investigate the targeting and potential neuroprotective effect of retrograde AdV-mediated BDNF gene transfection in the chronically compressed spinal cord in terms of prevention of apoptosis of neurons and oligodendrocytes. Several studies have investigated the neuroprotective effects of neurotrophins, including BDNF, in spinal cord injury. However, no report has described the effects of retrograde neurotrophic factor gene delivery in compressed spinal cords, including gene targeting and the potential to prevent neural cell apoptosis. AdV-BDNF or AdV-LacZ (as a control gene) was injected into the bilateral sternomastoid muscles of 18-week old twy/twy mice for retrograde gene delivery via the spinal accessory motor neurons. Heterozygous Institute of Cancer Research mice (+/twy), which do not undergo spontaneous spinal compression, were used as a control for the effects of such compression on gene delivery. The localization and cell specificity of β-galactosidase expression (produced by LacZ gene transfection) and BDNF expression in the spinal cord were examined by coimmunofluorescence staining for neural cell markers (NeuN, neurons; reactive immunology protein, oligodendrocytes; glial fibrillary acidic protein, astrocytes; OX-42, microglia) 4 weeks after gene injection. The possible neuroprotection afforded by retrograde AdV-BDNF gene delivery versus AdV-LacZ-transfected control mice was assessed by scoring the prevalence of apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) and immunoreactivity to active caspases -3, -8, and -9, p75, neurofilament 200 kD (NF), and for the oligodendroglial progenitor marker, NG2. RESULTS

GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986.

PubMed

Gupta, S K; Mishra, R; Kusum, S; Spedding, M; Meiri, K F; Gressens, P; Mani, S

2009-04-01

Positive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor modulators include benzamide compounds that allosterically modulate AMPA glutamate receptors. These small molecules that cross the blood-brain barrier have been shown to act as a neuroprotectant by increasing the levels of endogenous brain-derived neurotrophic factor (BDNF). Positive AMPA receptor modulators have also been shown to increase the levels of growth-associated protein-43 (GAP-43). GAP-43 plays a major role in many aspects of neuronal function in vertebrates. The goal of this study was to determine whether GAP-43 was important in mediating the actions of positive AMPA receptor modulator (S18986) and BDNF. Using cortical cultures from GAP-43 knockout and control mice, we show that (1) GAP-43 is upregulated in response to S18986 and BDNF in control cultures; (2) this upregulation of GAP-43 is essential for mediating the neuroprotective effects of S18986 and BDNF; (3) administration of S18986 and BDNF leads to an increase in the expression of the glutamate transporters GLT-1 and GLAST that are key to limiting excitotoxic cell death and this increase in GLT-1 and GLAST expression is completely blocked in the absence of GAP-43. Taken together this study concludes that GAP-43 is an important mediator of the neurotrophic effects of S18986 and BDNF on neuronal survival and plasticity, and is essential for the success of positive AMPA receptor modulator-BDNF-based neurotrophin therapy.

Genotypes do not confer risk for delinquency but rather alter susceptibility to positive and negative environmental factors: gene-environmentinteractions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR [corrected].

PubMed

Nilsson, Kent W; Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

2014-12-10

Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17-18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. © The Author 2015. Published by Oxford University

Genotypes Do Not Confer Risk For Delinquency ut Rather Alter Susceptibility to Positive and Negative Environmental Factors: Gene-Environment Interactions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR

PubMed Central

Comasco, Erika; Hodgins, Sheilagh; Oreland, Lars; Åslund, Cecilia

2015-01-01

Background: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5-HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. Methods: In 2006, as part of the Survey of Adolescent Life in Västmanland, Sweden, 1 337 high-school students, aged 17–18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. Results: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four-way interactions were found for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × family conflicts and for BDNF Val66Met × 5-HTTLPR×MAOA-uVNTR × sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met × 5-HTTLPR S × MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. Conclusions: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID

Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience.

PubMed

Yang, Bangkun; Yang, Chun; Ren, Qian; Zhang, Ji-Chun; Chen, Qian-Xue; Shirayama, Yukihiko; Hashimoto, Kenji

2016-12-01

Using learned helplessness (LH) model of depression, we measured protein expression of brain-derived neurotrophic factor (BDNF) pro-peptide, BDNF precursors (proBDNF and preproBDNF) in the brain regions of LH (susceptible) and non-LH rats (resilience). Expression of preproBDNF, proBDNF and BDNF pro-peptide in the medial prefrontal cortex of LH rats, but not non-LH rats, was significantly higher than control rats, although expression of these proteins in the nucleus accumbens of LH rats was significantly lower than control rats. This study suggests that regional differences in conversion of BDNF precursors into BDNF and BDNF pro-peptide by proteolytic cleavage may contribute to stress resilience.

Knockdown of long noncoding antisense RNA brain-derived neurotrophic factor attenuates hypoxia/reoxygenation-induced nerve cell apoptosis through the BDNF-TrkB-PI3K/Akt signaling pathway.

PubMed

Zhong, Jian-Bin; Li, Xie; Zhong, Si-Ming; Liu, Jiu-Di; Chen, Chi-Bang; Wu, Xiao-Yan

2017-09-27

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal cell apoptosis. The antisense RNA of brain-derived neurotrophic factor (BDNF-AS) is a natural antisense transcript that is transcribed opposite the gene that encodes BDNF. The aim of this study was to determine whether knockdown of BDNF-AS can suppress hypoxia/reoxygenation (H/R)-induced neuronal cell apoptosis and whether this is mediated by the BDNF-TrkB-PI3K/Akt pathway. We detected the expression of BDNF and BDNF-AS in brain tissue from 20 patients with cerebral infarction and five patients with other diseases (but no cerebral ischemia). We found that BDNF expression was significantly downregulated in patients with cerebral infarction, whereas the expression of BDNF-AS was significantly upregulated. In both human cortical neurons (HCN2) and human astrocytes, H/R significantly induced the expression of BDNF-AS, but significantly decreased BDNF expression. H/R also significantly induced apoptosis and reduced the mitochondrial membrane potential in these cells. Following downregulation of BDNF-AS by siRNA in human cortical neurons and human astrocyte cells, BDNF expression was significantly upregulated and the H/R-induced upregulation of BDNF-AS was significantly attenuated. BDNF-AS siRNA inhibited H/R-induced cell apoptosis and ameliorated the H/R-induced suppression of mitochondrial membrane potential. H/R inhibited the expression of BDNF, p-AKT/AKT, and TrKB, and this inhibition was recovered by BDNF-AS siRNA. In summary, this study indicates that BDNF-AS siRNA induces activation of the BDNF-TrkB-PI3K/Akt pathway following H/R-induced neurotoxicity. These findings will be useful toward the application of BDNF-AS siRNA for the treatment of neurodegenerative diseases.

Expression and methylation of BDNF in the human brain in schizophrenia.

PubMed

Cheah, Sern-Yih; McLeay, Robert; Wockner, Leesa F; Lawford, Bruce R; Young, Ross McD; Morris, Charles P; Voisey, Joanne

2017-08-01

To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene. DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex samples from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing. Expression, methylation and genotype data were correlated and examined for association with schizophrenia. There was 43% more of the BDNF V-VIII-IX transcript in schizophrenia samples. BDNF mRNA expression and DNA methylation of seven CpG sites were not associated with schizophrenia after accounting for age and PMI effects. BDNF mRNA expression and DNA methylation were not altered by Val66Met after accounting for age and PMI effects. DNA methylation of one CpG site had a marginally significant positive correlation with mRNA expression in schizophrenia subjects. Schizophrenia risk was not associated with differential BDNF mRNA expression and DNA methylation. A larger age-matched cohort with comprehensive clinical history is required to accurately identify the effects of genotype, mRNA expression and DNA methylation on schizophrenia risk.

Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease.

PubMed

Chiang, Ming-Chang; Chen, Hui-Mei; Lee, Yi-Hsin; Chang, Hao-Hung; Wu, Yi-Chih; Soong, Bing-Wen; Chen, Chiung-Mei; Wu, Yih-Ru; Liu, Chin-San; Niu, Dau-Ming; Wu, Jer-Yuarn; Chen, Yuan-Tsong; Chern, Yijuang

2007-03-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPalpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.

Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats.

PubMed

Peterson, Alexis B; Abel, Jean M; Lynch, Wendy J

2014-04-01

Physical activity, and specifically exercise, has shown promise as an intervention for drug addiction; however, the exercise conditions that produce the most efficacious response, as well as its underlying mechanism, are unknown. In this study, we examined the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking and associated changes in prefrontal cortex (PFC) brain-derived neurotrophic factor (Bdnf) exon IV expression, a marker of epigenetic regulation implicated in cocaine relapse and known to be regulated by exercise. Cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure following extended access cocaine or saline self-administration (24-h/day, 4 discrete trials/h, 10 days, 1.5 mg/kg/infusion) and a 14-day abstinence period. During abstinence, rats had either locked or unlocked running wheel access for 1, 2, or 6 h/day. Bdnf exon IV expression was assessed using quantitative real-time polymerase chain reaction. Cocaine-seeking was highest under the locked wheel condition, and wheel running dose dependently attenuated this effect. Cocaine increased Bdnf exon IV expression, and wheel running dose dependently attenuated this increase, with complete blockade in rats given 6-h/day access. Notably, the efficacy of exercise was inversely associated with Bdnf exon IV expression, and both its efficacy and its effects on Bdnf exon IV expression were mimicked by treatment during abstinence with sodium butyrate, a histone deacetylase inhibitor that, like exercise, modulates gene transcription, including Bdnf exon IV expression. Taken together, these results indicate that the efficacy of exercise is dose dependent and likely mediated through epigenetic regulation of PFC Bdnf.

Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.

PubMed

Sleiman, Sama F; Henry, Jeffrey; Al-Haddad, Rami; El Hayek, Lauretta; Abou Haidar, Edwina; Stringer, Thomas; Ulja, Devyani; Karuppagounder, Saravanan S; Holson, Edward B; Ratan, Rajiv R; Ninan, Ipe; Chao, Moses V

2016-06-02

Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF.

BDNF Up-Regulates α7 Nicotinic Acetylcholine Receptor Levels on Subpopulations of Hippocampal Interneurons

PubMed Central

Massey, Kerri A.; Zago, Wagner M.; Berg, Darwin K.

2006-01-01

In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of α7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the effect. Blocking transmission through NMDA receptors with APV blocked the BDNF effect; increasing spontaneous excitatory activity with the GABAA receptor antagonist bicuculline replicated the BDNF effect. BDNF antibodies blocked the BDNF-mediated increase but not the bicuculline one, consistent with enhanced glutamatergic activity acting downstream from BDNF. Increased α7-nAChR clusters were most prominent on interneuron subtypes known to innervate directly excitatory neurons. The results suggest that BDNF, acting through glutamatergic transmission, can modulate hippocampal output in part by controlling α7-nAChR levels. PMID:17029981

Modulation of mutant Huntingtin aggregates and toxicity by human myeloid leukemia factors.

PubMed

Banerjee, Manisha; Datta, Moumita; Bhattacharyya, Nitai P

2017-01-01

Increased poly glutamine (polyQ) stretch at N-terminal of Huntingtin (HTT) causes Huntington's disease. HTT interacts with large number of proteins, although the preference for such interactions with wild type or mutated HTT protein remains largely unknown. HYPK, an intrinsically unstructured protein chaperone and interactor of mutant HTT was found to interact with myeloid leukemia factor 1 (MLF1) and 2 (MLF2). To identify the role of these two proteins in mutant HTT mediated aggregate formation and toxicity in a cell model, both the proteins were found to preferentially interact with the mutated N-terminal HTT. They significantly reduced the number of cells containing mutant HTT aggregates and subsequent apoptosis in Neuro2A cells. Additionally, in FRAP assay, mobile fraction of mutant HTT aggregates was increased in the presence of MLF1 or MLF2. Further, MLF1 could release transcription factors like p53, CBP and CREB from mutant HTT aggregates. Moreover, in HeLa cell co-expressing mutant HTT exon1 and full length MLF1, p53 was released from the aggregates, leading to the recovery of the expression of the GADD45A transcript, a p53 regulated gene. Taking together, these results showed that MLF1 and MLF2 modulated the formation of aggregates and induction of apoptosis as well as the expressions of genes indirectly. Copyright © 2016 Elsevier Ltd. All rights reserved.

Influence of BDNF and COMT polymorphisms on emotional decision making.

PubMed

Kang, Jee In; Namkoong, Kee; Ha, Ra Yeon; Jhung, Kyungun; Kim, Yang Tae; Kim, Se Joo

2010-06-01

Decision making is an important brain function. Although little is known about the genetic basis of decision making, it has been suggested that it is mediated by the modulation of neurotransmitter systems. We investigated how the BDNF Val66Met and COMT Val158Met polymorphisms affect emotional decision making using the Iowa Gambling Task (IGT). One hundred sixty-eight healthy Korean college students (93 males, 75 females) with a complete dataset were included in the data analysis. The IGT and genotyping for the polymorphisms of BDNF Val66Met and COMT Val158Met were performed. Both Met/Met and Val/Met of the BDNF Val66Met polymorphism were significantly associated with a lower mean score of blocks 3-5 of the IGT and with less improvement from block 1 to block 3-5 than the Val/Val. However, the BDNF was not significantly associated with the score of block 1, and the COMT Val158Met polymorphism produced no significant effect on IGT performance. No interaction effect was observed between the BDNF and the COMT for the IGT. These findings suggest the BDNF Val66Met may affect the emotional decision making performance. (c) 2010 Elsevier Ltd. All rights reserved.

Deficiency of Huntingtin Has Pleiotropic Effects in the Social Amoeba Dictyostelium discoideum

PubMed Central

Myre, Michael A.; Lumsden, Amanda L.; Thompson, Morgan N.; Wasco, Wilma; MacDonald, Marcy E.; Gusella, James F.

2011-01-01

Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington's disease (HD). Genetic evidence in humans and knock-in mouse models suggests that this gain-of-function involves an increase or deregulation of some aspect of huntingtin's normal function(s), which remains poorly understood. As huntingtin shows evolutionary conservation, a powerful approach to discovering its normal biochemical role(s) is to study the effects caused by its deficiency in a model organism with a short life-cycle that comprises both cellular and multicellular developmental stages. To facilitate studies aimed at detailed knowledge of huntingtin's normal function(s), we generated a null mutant of hd, the HD ortholog in Dictyostelium discoideum. Dictyostelium cells lacking endogenous huntingtin were viable but during development did not exhibit the typical polarized morphology of Dictyostelium cells, streamed poorly to form aggregates by accretion rather than chemotaxis, showed disorganized F-actin staining, exhibited extreme sensitivity to hypoosmotic stress, and failed to form EDTA-resistant cell–cell contacts. Surprisingly, chemotactic streaming could be rescued in the presence of the bivalent cations Ca2+ or Mg2+ but not pulses of cAMP. Although hd − cells completed development, it was delayed and proceeded asynchronously, producing small fruiting bodies with round, defective spores that germinated spontaneously within a glassy sorus. When developed as chimeras with wild-type cells, hd − cells failed to populate the pre-spore region of the slug. In Dictyostelium, huntingtin deficiency is compatible with survival of the organism but renders cells sensitive to low osmolarity, which produces pleiotropic cell autonomous defects that affect cAMP signaling and as a consequence development. Thus, Dictyostelium provides a novel haploid

Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2).

PubMed

Ross, T S; Bernard, O A; Berger, R; Gilliland, D G

1998-06-15

We report the fusion of the Huntingtin interactin protein 1 (HIP1) gene to the platelet-derived growth factor betareceptor (PDGFbetaR) gene in a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation. Southern blot analysis of patient bone marrow cells with a PDGFbetaR gene probe demonstrated rearrangement of the PDGFbetaR gene. Anchored polymerase chain reaction using PDGFbetaR primers identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFbetaR gene on 5q33. HIP1 is a 116-kD protein recently cloned by yeast two-hybrid screening for proteins that interact with Huntingtin, the mutated protein in Huntington's disease. The consequence of t(5;7)(q33;q11.2) is an HIP1/PDGFbetaR fusion gene that encodes amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFbetaR. The reciprocal PDGFbetaR/HIP1 transcript is not expressed. HIP1/PDGFbetaR is a 180-kD protein when expressed in the murine hematopoietic cell line, Ba/F3, and is constitutively tyrosine phosphorylated. Furthermore, HIP1/PDGFbetaR transforms the Ba/F3 cells to interleukin-3-independent growth. These data are consistent with an alternative mechanism for activation of PDGFbetaR tyrosine kinase activity by fusion with HIP1, leading to transformation of hematopoietic cells, and may implicate Huntingtin or HIP1 in the pathogenesis of hematopoietic malignancies.

The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients.

PubMed

Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-02-02

BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.

The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese heroin-dependent patients

PubMed Central

Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Wang, Tzu-Yun; Chen, Shih-Heng; Chu, Chun-Hsien; Chen, Po See; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-01-01

BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency. PMID:25640280

Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain-liver axis.

PubMed

Yang, B; Ren, Q; Zhang, J-C; Chen, Q-X; Hashimoto, K

2017-05-16

Brain-derived neurotrophic factor (BDNF) has a role in the pathophysiology of psychiatric disorders. The precursor proBDNF is converted to mature BDNF and BDNF pro-peptide, the N-terminal fragment of proBDNF; however, the precise function of these proteins in psychiatric disorders is unknown. We sought to determine whether expression of these proteins is altered in the brain and peripheral tissues from patients with psychiatric disorders. We measured protein expression of proBDNF, mature BDNF and BDNF pro-peptide in the parietal cortex, cerebellum, liver and spleen from control, major depressive disorder (MDD), schizophrenia (SZ) and bipolar disorder (BD) groups. The levels of mature BDNF in the parietal cortex from MDD, SZ and BD groups were significantly lower than the control group, whereas the levels of BDNF pro-peptide in this area were significantly higher than controls. In contrast, the levels of proBDNF and BDNF pro-peptide in the cerebellum of MDD, SZ and BD groups were significantly lower than controls. Moreover, the levels of mature BDNF from the livers of MDD, SZ and BD groups were significantly higher than the control group. The levels of mature BDNF in the spleen did not differ among the four groups. Interestingly, there was a negative correlation between mature BDNF in the parietal cortex and mature BDNF in the liver in all the subjects. These findings suggest that abnormalities in the production of mature BDNF and BDNF pro-peptide in the brain and liver might have a role in the pathophysiology of psychiatric disorders, indicating a brain-liver axis in psychiatric disorders.

Regulation of BDNF chromatin status and promoter accessibility in a neural correlate of associative learning

PubMed Central

Ambigapathy, Ganesh; Zheng, Zhaoqing; Keifer, Joyce

2015-01-01

Brain-derived neurotrophic factor (BDNF) gene expression critically controls learning and its aberrant regulation is implicated in Alzheimer's disease and a host of neurodevelopmental disorders. The BDNF gene is target of known DNA regulatory mechanisms but details of its activity-dependent regulation are not fully characterized. We performed a comprehensive analysis of the epigenetic regulation of the turtle BDNF gene (tBDNF) during a neural correlate of associative learning using an in vitro model of eye blink classical conditioning. Shortly after conditioning onset, the results from ChIP-qPCR show conditioning-dependent increases in methyl-CpG-binding protein 2 (MeCP2) and repressor basic helix-loop-helix binding protein 2 (BHLHB2) binding to tBDNF promoter II that corresponds with transcriptional repression. In contrast, enhanced binding of ten-eleven translocation protein 1 (Tet1), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP response element-binding protein (CREB) to promoter III corresponds with transcriptional activation. These actions are accompanied by rapid modifications in histone methylation and phosphorylation status of RNA polymerase II (RNAP II). Significantly, these remarkably coordinated changes in epigenetic factors for two alternatively regulated tBDNF promoters during conditioning are controlled by Tet1 and ERK1/2. Our findings indicate that Tet1 and ERK1/2 are critical partners that, through complementary functions, control learning-dependent tBDNF promoter accessibility required for rapid transcription and acquisition of classical conditioning. PMID:26336984

BDNF/TrkB Pathway Mediates the Antidepressant-Like Role of H2S in CUMS-Exposed Rats by Inhibition of Hippocampal ER Stress.

PubMed

Wei, Le; Kan, Li-Yuan; Zeng, Hai-Ying; Tang, Yi-Yun; Huang, Hong-Lin; Xie, Ming; Zou, Wei; Wang, Chun-Yan; Zhang, Ping; Tang, Xiao-Qing

2018-06-01

Our previous works have shown that hydrogen sulfide (H 2 S) significantly attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and hippocampal endoplasmic reticulum (ER) stress. Brain-derived neurotrophic factor (BDNF) generates an antidepressant-like effect by its receptor tyrosine protein kinase B (TrkB). We have previously found that H 2 S upregulates the expressions of BDNF and p-TrkB in the hippocampus of CUMS-exposed rats. Therefore, the present work was to explore whether BDNF/TrkB pathway mediates the antidepressant-like role of H 2 S by blocking hippocampal ER stress. We found that treatment with K252a (an inhibitor of BDNF/TrkB pathway) significantly increased the immobility time in the forced swim test and tail suspension test and increased the latency to feed in the novelty-suppressed feeding test in the rats cotreated with sodium hydrosulfide (NaHS, a donor of H 2 S) and CUMS. Similarly, K252a reversed the protective effect of NaHS against CUMS-induced hippocampal ER stress, as evidenced by increases in the levels of ER stress-related proteins, glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12. Taken together, our results suggest that BDNF/TrkB pathway plays an important mediatory role in the antidepressant-like action of H 2 S in CUMS-exposed rats, which is by suppression of hippocampal ER stress. These data provide a novel mechanism underlying the protection of H 2 S against CUMS-induced depressive-like behaviors.

Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment.

PubMed

Diniz, Cassiano R A F; Casarotto, Plinio C; Resstel, Leonardo; Joca, Sâmia R L

2018-04-04

Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the "continuum-sorting hypothesis." The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress. Copyright © 2018 Elsevier Ltd. All rights reserved.

The Neuroprotective Role of Acupuncture and Activation of the BDNF Signaling Pathway

PubMed Central

Lin, Dong; De La Pena, Ike; Lin, Lili; Zhou, Shu-Feng; Borlongan, Cesar V.; Cao, Chuanhai

2014-01-01

Recent studies have been conducted to examine the neuroprotective effects of acupuncture in many neurological disorders. Although the neuroprotective effects of acupuncture has been linked to changes in signaling pathways, accumulating evidence suggest the participation of endogenous biological mediators, such as the neurotrophin (NT) family of proteins, specifically, the brain derived neurotrophic factor (BDNF). Accordingly, acupuncture can inhibit neurodegeneration via expression and activation of BDNF. Moreover, recent studies have reported that acupuncture can increase ATP levels at local stimulated points. We have also demonstrated that acupuncture could activate monocytes and increase the expression of BDNF via the stimulation of ATP. The purpose of this article is to review the recent findings and ongoing studies on the neuroprotective roles of acupuncture and therapeutic implications of acupuncture-induced activation of BDNF and its signaling pathway. PMID:24566146

Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration.

PubMed

Creus-Muncunill, Jordi; Rué, Laura; Alcalá-Vida, Rafael; Badillos-Rodríguez, Raquel; Romaní-Aumedes, Joan; Marco, Sonia; Alberch, Jordi; Perez-Otaño, Isabel; Malagelada, Cristina; Pérez-Navarro, Esther

2018-02-19

Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death. Here, we analyzed whether mTORC2 activity could be altered by the presence of mutant huntingtin. We observed that Rictor levels are specifically increased in the striatum of HD mouse models and in the putamen of HD patients. Rictor-mTOR interaction and the phosphorylation levels of Akt, one of the targets of the mTORC2 complex, were increased in the striatum of the R6/1 mouse model of HD suggesting increased mTORC2 signaling. Interestingly, acute downregulation of Rictor in striatal cells in vitro reduced mTORC2 activity, as shown by reduced levels of phospho-Akt, and increased mutant huntingtin-induced cell death. Accordingly, overexpression of Rictor increased mTORC2 activity counteracting cell death. Furthermore, normalization of endogenous Rictor levels in the striatum of R6/1 mouse worsened motor symptoms suggesting an induction of neuronal dysfunction. In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin.

The BDNF Val66Met polymorphism and plasma brain-derived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia.

PubMed

Chen, Shiou-Lan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Tzu-Yun; Chen, Po-See; Lee, I-Hui; Yang, Yen-Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2014-06-03

Brain-derived neurotropic factor (BDNF) is widely distributed in the peripheral and central nervous systems. BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of several mental illnesses. To elucidate the role of BDNF, we compared the plasma BDNF levels and the BDNF Val66Met gene variants effect in several mental disorders. We enrolled 644 participants: 177 patients with bipolar I disorder (BP-I), 190 with bipolar II disorder (BP-II), 151 with schizophrenia, and 126 healthy controls. Their plasma BDNF levels and BDNF Val66Met single nucleotide polymorphisms (SNP) were checked before pharmacological treatment. Plasma levels of BDNF were significantly lower in patients with schizophrenia than in healthy controls and patients with bipolar disorder (F = 37.667, p<0.001); the distribution of the BDNF Val66Met SNP was not different between groups (χ(2) = 5.289, p = 0.507). Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not influence plasma BDNF levels in our participants. Plasma BDNF levels were, however, significantly negatively correlated with depression scores in patients with bipolar disorder and with negative symptoms in patients with schizophrenia. We conclude that plasma BDNF profiles in different mental disorders are not affected by BDNF Val66Met gene variants, but by the process and progression of the illness itself. Copyright © 2014 Elsevier Inc. All rights reserved.

Plasma BDNF Concentration, Val66Met Genetic Variant, and Depression-Related Personality Traits

PubMed Central

Terracciano, Antonio; Martin, Bronwen; Ansari, David; Tanaka, Toshiko; Ferrucci, Luigi; Maudsley, Stuart; Mattson, Mark P.; Costa, Paul T.

2010-01-01

Brain derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurogenesis, and BDNF plasma and serum levels have been associated with depression, Alzheimer's disease, and other psychiatric and neurodegenerative disorders. In a relatively large community sample, drawn from the Baltimore Longitudinal Study of Aging (BLSA), we examine whether BDNF plasma concentration is associated with the Val66Met functional polymorphism of the BDNF gene (n = 335) and with depression-related personality traits assessed with the NEO-PI-R (n = 391). Plasma concentration of BDNF was not associated with the Val66Met variant in either men or women. However, in men, but not in women, BDNF plasma level was associated with personality traits linked to depression. Contrary to the notion that low BDNF is associated with negative outcomes, we found lower plasma levels in men who score lower on depression and vulnerability to stress (two facets of Neuroticism) and higher on Conscientiousness and Extraversion. These findings challenge the prevailing hypothesis that lower peripheral levels of BDNF are a marker of depression. PMID:20345896

HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.

PubMed

Metzler, M; Legendre-Guillemin, V; Gan, L; Chopra, V; Kwok, A; McPherson, P S; Hayden, M R

2001-10-19

Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington disease. This mutation influences the interaction of huntingtin with different proteins, including huntingtin-interacting protein 1 (HIP1), in which affinity to bind to mutant huntingtin is profoundly reduced. Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276-335. This region, which contains consensus clathrin- and AP2-binding sites, functions in conjunction with the coiled-coil domain to target HIP1 to CCVs. Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery.

The CB₁ cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway.

PubMed

Blázquez, C; Chiarlone, A; Bellocchio, L; Resel, E; Pruunsild, P; García-Rincón, D; Sendtner, M; Timmusk, T; Lutz, B; Galve-Roperh, I; Guzmán, M

2015-10-01

The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival.

Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia.

PubMed

Forero, Diego A; Benítez, Bruno; Arboleda, Gonzalo; Yunis, Juan J; Pardo, Rodrigo; Arboleda, Humberto

2006-07-01

In recent years, it has been proposed that synaptic dysfunction may be an important etiological factor for Alzheimer's disease (AD). This hypothesis has important implications for the analysis of AD genetic risk in case-control studies. In the present work, we analyzed common functional polymorphisms in three synaptic plasticity-related genes (brain-derived neurotrophic factor, BDNF Val66Met; catechol-O-methyl transferase, COMT Val158; ubiquitin carboxyl-terminal hydroxylase, UCHL1 S18Y) in a sample of 102 AD cases and 168 age and sex matched controls living in Bogotá, Colombia. There was not association between UCHL1 polymorphism and AD in our sample. We have found an initial association with BDNF polymorphism in familial cases and with COMT polymorphism in male and sporadic patients. These initial associations were lost after Bonferroni correction for multiple testing. Unadjusted results may be compatible with the expected functional effect of variations in these genes on pathological memory and cognitive dysfunction, as has been implicated in animal and cell models and also from neuropsychological analysis of normal subjects carriers of the AD associated genotypes. An exploration of functional variants in these and in other synaptic plasticity-related genes (a synaptogenomics approach) in independent larger samples will be important to discover new genes associated with AD.

Predicting Response Trajectories during Cognitive-Behavioural Therapy for Panic Disorder: No Association with the BDNF Gene or Childhood Maltreatment.

PubMed

Santacana, Martí; Arias, Bárbara; Mitjans, Marina; Bonillo, Albert; Montoro, María; Rosado, Sílvia; Guillamat, Roser; Vallès, Vicenç; Pérez, Víctor; Forero, Carlos G; Fullana, Miquel A

2016-01-01

Anxiety disorders are highly prevalent and result in low quality of life and a high social and economic cost. The efficacy of cognitive-behavioural therapy (CBT) for anxiety disorders is well established, but a substantial proportion of patients do not respond to this treatment. Understanding which genetic and environmental factors are responsible for this differential response to treatment is a key step towards "personalized medicine". Based on previous research, our objective was to test whether the BDNF Val66Met polymorphism and/or childhood maltreatment are associated with response trajectories during exposure-based CBT for panic disorder (PD). We used Growth Mixture Modeling to identify latent classes of change (response trajectories) in patients with PD (N = 97) who underwent group manualized exposure-based CBT. We conducted logistic regression to investigate the effect on these trajectories of the BDNF Val66Met polymorphism and two different types of childhood maltreatment, abuse and neglect. We identified two response trajectories ("high response" and "low response"), and found that they were not significantly associated with either the genetic (BDNF Val66Met polymorphism) or childhood trauma-related variables of interest, nor with an interaction between these variables. We found no evidence to support an effect of the BDNF gene or childhood trauma-related variables on CBT outcome in PD. Future studies in this field may benefit from looking at other genotypes or using different (e.g. whole-genome) approaches.

Interaction with Polyglutamine-expanded Huntingtin Alters Cellular Distribution and RNA Processing of Huntingtin Yeast Two-hybrid Protein A (HYPA)*

PubMed Central

Jiang, Ya-Jun; Che, Mei-Xia; Yuan, Jin-Qiao; Xie, Yuan-Yuan; Yan, Xian-Zhong; Hu, Hong-Yu

2011-01-01

Huntington disease (HD) is an autosomal inherited disorder that causes the deterioration of brain cells. The polyglutamine (polyQ) expansion of huntingtin (Htt) is implicated in the pathogenesis of HD via interaction with an RNA splicing factor, Htt yeast two-hybrid protein A/forming-binding protein 11 (HYPA/FBP11). Besides the pathogenic polyQ expansion, Htt also contains a proline-rich region (PRR) located exactly in the C terminus to the polyQ tract. However, how the polyQ expansion influences the PRR-mediated protein interaction and how this abnormal interaction leads to the biological consequence remain elusive. Our NMR structural analysis indicates that the PRR motif of Htt cooperatively interacts with the tandem WW domains of HYPA through domain chaperoning effect of WW1 on WW2. The polyQ-expanded Htt sequesters HYPA to the cytosolic location and then significantly reduces the efficiency of pre-mRNA splicing. We propose that the toxic gain-of-function of the polyQ-expanded Htt that causes dysfunction of cellular RNA processing contributes to the pathogenesis of HD. PMID:21566141

Interaction with polyglutamine-expanded huntingtin alters cellular distribution and RNA processing of huntingtin yeast two-hybrid protein A (HYPA).

PubMed

Jiang, Ya-Jun; Che, Mei-Xia; Yuan, Jin-Qiao; Xie, Yuan-Yuan; Yan, Xian-Zhong; Hu, Hong-Yu

2011-07-15

Huntington disease (HD) is an autosomal inherited disorder that causes the deterioration of brain cells. The polyglutamine (polyQ) expansion of huntingtin (Htt) is implicated in the pathogenesis of HD via interaction with an RNA splicing factor, Htt yeast two-hybrid protein A/forming-binding protein 11 (HYPA/FBP11). Besides the pathogenic polyQ expansion, Htt also contains a proline-rich region (PRR) located exactly in the C terminus to the polyQ tract. However, how the polyQ expansion influences the PRR-mediated protein interaction and how this abnormal interaction leads to the biological consequence remain elusive. Our NMR structural analysis indicates that the PRR motif of Htt cooperatively interacts with the tandem WW domains of HYPA through domain chaperoning effect of WW1 on WW2. The polyQ-expanded Htt sequesters HYPA to the cytosolic location and then significantly reduces the efficiency of pre-mRNA splicing. We propose that the toxic gain-of-function of the polyQ-expanded Htt that causes dysfunction of cellular RNA processing contributes to the pathogenesis of HD.

Localization of BDNF expression in the developing brain of zebrafish

PubMed Central

De Felice, E; Porreca, I; Alleva, E; De Girolamo, P; Ambrosino, C; Ciriaco, E; Germanà, A; Sordino, P

2014-01-01

The brain-derived neurotrophic factor (BDNF) gene is expressed in differentiating and post-mitotic neurons of the zebrafish embryo, where it has been implicated in Huntington's disease. Little is known, however, about the full complement of neuronal cell types that express BDNF in this important vertebrate model. Here, we further explored the transcriptional profiles during the first week of development using real-time quantitative polymerase chain reaction (RT-qPCR) and whole-mount in situ hybridization (WISH). RT-qPCR results revealed a high level of maternal contribution followed by a steady increase of zygotic transcription, consistent with the notion of a prominent role of BDNF in neuronal maturation and maintenance. Based on WISH, we demonstrate for the first time that BDNF expression in the developing brain of zebrafish is structure specific. Anatomical criteria and co-staining with genetic markers (shh, pax2a, emx1, krox20, lhx2b and lhx9) visualized major topological domains of BDNF-positive cells in the pallium, hypothalamus, posterior tuberculum and optic tectum. Moreover, the relative timing of BDNF transcription in the eye and tectum may illustrate a mechanism for coordinated development of the retinotectal system. Taken together, our results are compatible with a local delivery and early role of BDNF in the developing brain of zebrafish, adding basic knowledge to the study of neurotrophin functions in neural development and disease. PMID:24588510

BDNF Expression in Larval and Adult Zebrafish Brain: Distribution and Cell Identification

PubMed Central

Cacialli, Pietro; Gueguen, Marie-Madeleine; Coumailleau, Pascal; D’Angelo, Livia; Kah, Olivier; Lucini, Carla; Pellegrini, Elisabeth

2016-01-01

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has emerged as an active mediator in many essential functions in the central nervous system of mammals. BDNF plays significant roles in neurogenesis, neuronal maturation and/or synaptic plasticity and is involved in cognitive functions such as learning and memory. Despite the vast literature present in mammals, studies devoted to BDNF in the brain of other animal models are scarse. Zebrafish is a teleost fish widely known for developmental genetic studies and is emerging as model for translational neuroscience research. In addition, its brain shows many sites of adult neurogenesis allowing higher regenerative properties after traumatic injuries. To add further knowledge on neurotrophic factors in vertebrate brain models, we decided to determine the distribution of bdnf mRNAs in the larval and adult zebrafish brain and to characterize the phenotype of cells expressing bdnf mRNAs by means of double staining studies. Our results showed that bdnf mRNAs were widely expressed in the brain of 7 days old larvae and throughout the whole brain of mature female and male zebrafish. In adults, bdnf mRNAs were mainly observed in the dorsal telencephalon, preoptic area, dorsal thalamus, posterior tuberculum, hypothalamus, synencephalon, optic tectum and medulla oblongata. By combining immunohistochemistry with in situ hybridization, we showed that bdnf mRNAs were never expressed by radial glial cells or proliferating cells. By contrast, bdnf transcripts were expressed in cells with neuronal phenotype in all brain regions investigated. Our results provide the first demonstration that the brain of zebrafish expresses bdnf mRNAs in neurons and open new fields of research on the role of the BDNF factor in brain mechanisms in normal and brain repairs situations. PMID:27336917

The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis.

PubMed

Waelter, S; Scherzinger, E; Hasenbank, R; Nordhoff, E; Lurz, R; Goehler, H; Gauss, C; Sathasivam, K; Bates, G P; Lehrach, H; Wanker, E E

2001-08-15

The huntingtin interacting protein (HIP1) is enriched in membrane-containing cell fractions and has been implicated in vesicle trafficking. It is a multidomain protein containing an N-terminal ENTH domain, a central coiled-coil forming region and a C-terminal actin-binding domain. In the present study we have identified three HIP1 associated proteins, clathrin heavy chain and alpha-adaptin A and C. In vitro binding studies revealed that the central coiled-coil domain is required for the interaction of HIP1 with clathrin, whereas DPF-like motifs located upstream to this domain are important for the binding of HIP1 to the C-terminal 'appendage' domain of alpha-adaptin A and C. Expression of full length HIP1 in mammalian cells resulted in a punctate cytoplasmic immunostaining characteristic of clathrin-coated vesicles. In contrast, when a truncated HIP1 protein containing both the DPF-like motifs and the coiled-coil domain was overexpressed, large perinuclear vesicle-like structures containing HIP1, huntingtin, clathrin and endocytosed transferrin were observed, indicating that HIP1 is an endocytic protein, the structural integrity of which is crucial for maintenance of normal vesicle size in vivo.

Lack of promoter IV-driven BDNF transcription results in depression-like behavior.

PubMed

Sakata, K; Jin, L; Jha, S

2010-10-01

Transcription of Bdnf is controlled by multiple promoters, in which promoter IV contributes significantly to activity-dependent Bdnf transcription. We have generated promoter IV mutant mice [brain-derived neurotrophic factor (BDNF)-KIV] in which promoter IV-driven expression of BDNF is selectively disrupted by inserting a green fluorescent protein (GFP)-STOP cassette within the Bdnf exon IV locus. BDNF-KIV animals exhibited depression-like behavior as shown by the tail suspension test (TST), sucrose preference test (SPT) and learned helplessness test (LHT). In addition, BDNF-KIV mice showed reduced activity in the open field test (OFT) and reduced food intake in the novelty-suppressed feeding test (NSFT). The mutant mice did not display anxiety-like behavior in the light and dark box test and elevated plus maze tests. Interestingly, the mutant mice showed defective response inhibition in the passive avoidance test (PAT) even though their learning ability was intact when measured with the active avoidance test (AAT). These results suggest that promoter IV-dependent BDNF expression plays a critical role in the control of mood-related behaviors. This is the first study that directly addressed the effects of endogenous promoter-driven expression of BDNF in depression-like behavior. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Electrically evoked local muscle contractions cause an increase in hippocampal BDNF.

PubMed

Maekawa, Takahiro; Ogasawara, Riki; Tsutaki, Arata; Lee, Kihyuk; Nakada, Satoshi; Nakazato, Koichi; Ishii, Naokata

2018-05-01

High-intensity exercise has recently been shown to cause an increase in brain-derived neurotropic factor (BDNF) in the hippocampus. Some studies have suggested that myokines secreted from contracting skeletal muscle, such as irisin (one of the truncated form of fibronectin type III domain-containing protein 5 (FNDC5)), play important roles in this process. Thus, we hypothesized that locally evoked muscle contractions may cause an increase of BDNF in the hippocampus through some afferent mechanisms. Under anesthesia, Sprague-Dawley rats were fixed on a custom-made dynamometer and their triceps surae muscles were made to maximally contract via delivery of electric stimulations of the sciatic nerve (100 Hz with 1-ms pulse and 3-s duration). Following 50 repeated maximal isometric contractions, the protein expressions of BDNF and activation of its receptor in the hippocampus significantly increased compared with the sham-operated control rats. However, the expression of both BDNF and FNDC5 within stimulated muscles did not significantly increase, nor did their serum concentrations change. These results indicate that local muscular contractions under unconsciousness can induce BDNF expression in the hippocampus. This effect may be mediated by peripheral reception of muscle contraction, but not by systemic factors.

Inhibition of NMDA Receptors Prevents the Loss of BDNF Function Induced by Amyloid β.

PubMed

Tanqueiro, Sara R; Ramalho, Rita M; Rodrigues, Tiago M; Lopes, Luísa V; Sebastião, Ana M; Diógenes, Maria J

2018-01-01

Brain-derived neurotrophic factor (BDNF) plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. In Alzheimer's disease (AD), BDNF signaling is known to be impaired, partially because amyloid β (Aβ) induces truncation of BDNF main receptor, TrkB-full length (TrkB-FL). We have previously shown that such truncation is mediated by calpains, results in the formation of an intracellular domain (ICD) fragment and causes BDNF loss of function. Since calpains are Ca 2+ -dependent proteases, we hypothesized that excessive intracellular Ca 2+ build-up could be due to dysfunctional N-methyl-d-aspartate receptors (NMDARs) activation. To experimentally address this hypothesis, we investigated whether TrkB-FL truncation by calpains and consequent BDNF loss of function could be prevented by NMDAR blockade. We herein demonstrate that a NMDAR antagonist, memantine, prevented excessive calpain activation and TrkB-FL truncation induced by Aβ 25-35 . When calpains were inhibited by calpastatin, BDNF was able to increase the dendritic spine density of neurons exposed to Aβ 25135 . Moreover, NMDAR inhibition by memantine also prevented Aβ-driven deleterious impact of BDNF loss of function on structural (spine density) and functional outcomes (synaptic potentiation). Collectively, these findings support NMDAR/Ca 2+ /calpains mechanistic involvement in Aβ-triggered BDNF signaling disruption.

BDNF expression in the hippocampus of maternally separated rats: does Bifidobacterium breve 6330 alter BDNF levels?

PubMed

O'Sullivan, E; Barrett, E; Grenham, S; Fitzgerald, P; Stanton, C; Ross, R P; Quigley, E M M; Cryan, J F; Dinan, T G

2011-09-01

Brain-derived neurotrophic factor (BDNF) is of interest because of its putative role in stress and psychiatric disorders. Maternal separation is used as an animal model of early-life stress and of irritable bowel syndrome (IBS). Animals exposed to the paradigm show altered gut function together with heightened levels of arousal and corticosterone. Some probiotic organisms have been shown to be of benefit in IBS and influence the brain-gut axis. Our objective was to investigate the effects of maternal separation on BDNF under basal conditions and in response to the probiotic Bifidobacterium breve 6330. The study implemented the maternal separation model which we have previously described. Polymerase chain reaction and in situ hybridisation were performed to measure the effect of maternal separation on both BDNF total variants and BDNF splice variant (exon) IV in the hippocampus. Maternally separated and non-separated rats were treated with B. breve 6330, to investigate the effect of this probiotic on BDNF total variant and BDNF exon IV expression. Maternal separation increased BDNF total variants (P<0.01), whilst having no effect on BDNF exon IV. B. breve 6330 increased BDNF total variants (P<0.01), and decreased BDNF splice variant IV, in non-separated rats (P<0.01). B. breve 6330 did not alter BDNF levels in the maternally separated rats. Maternal separation caused a marked increase in BDNF in the hippocampus. While B. breve 6330 influenced BDNF in normal animals, it had no significant effect on BDNF in those which were maternally separated. We have demonstrated that an orally administered probiotic can influence hippocampal BDNF.

Neuroprotective Effects of Psychotropic Drugs in Huntington’s Disease

PubMed Central

Lauterbach, Edward C.

2013-01-01

Psychotropics (antipsychotics, mood stabilizers, antidepressants, anxiolytics, etc.) are commonly prescribed to treat Huntington’s disease (HD). In HD preclinical models, while no psychotropic has convincingly affected huntingtin gene, HD modifying gene, or huntingtin protein expression, psychotropic neuroprotective effects include upregulated huntingtin autophagy (lithium), histone acetylation (lithium, valproate, lamotrigine), miR-222 (lithium-plus-valproate), mitochondrial protection (haloperidol, trifluoperazine, imipramine, desipramine, nortriptyline, maprotiline, trazodone, sertraline, venlafaxine, melatonin), neurogenesis (lithium, valproate, fluoxetine, sertraline), and BDNF (lithium, valproate, sertraline) and downregulated AP-1 DNA binding (lithium), p53 (lithium), huntingtin aggregation (antipsychotics, lithium), and apoptosis (trifluoperazine, loxapine, lithium, desipramine, nortriptyline, maprotiline, cyproheptadine, melatonin). In HD live mouse models, delayed disease onset (nortriptyline, melatonin), striatal preservation (haloperidol, tetrabenazine, lithium, sertraline), memory preservation (imipramine, trazodone, fluoxetine, sertraline, venlafaxine), motor improvement (tetrabenazine, lithium, valproate, imipramine, nortriptyline, trazodone, sertraline, venlafaxine), and extended survival (lithium, valproate, sertraline, melatonin) have been documented. Upregulated CREB binding protein (CBP; valproate, dextromethorphan) and downregulated histone deacetylase (HDAC; valproate) await demonstration in HD models. Most preclinical findings await replication and their limitations are reviewed. The most promising findings involve replicated striatal neuroprotection and phenotypic disease modification in transgenic mice for tetrabenazine and for sertraline. Clinical data consist of an uncontrolled lithium case series (n = 3) suggesting non-progression and a primarily negative double-blind, placebo-controlled clinical trial of lamotrigine. PMID:24248060

Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine.

PubMed

Ando, Susumu; Kobayashi, Satoru; Waki, Hatsue; Kon, Kazuo; Fukui, Fumiko; Tadenuma, Tomoko; Iwamoto, Machiko; Takeda, Yasuo; Izumiyama, Naotaka; Watanabe, Kazutada; Nakamura, Hiroaki

2002-11-01

A rat dementia model with cognitive deficits was generated by synapse-specific lesions using botulinum neurotoxin (BoNTx) type B in the entorhinal cortex. To detect cognitive deficits, different tasks were needed depending upon the age of the model animals. Impaired learning and memory with lesions were observed in adult rats using the Hebb-Williams maze, AKON-1 maze and a continuous alternation task in T-maze. Cognitive deficits in lesioned aged rats were detected by a continuous alternation and delayed non-matching-to-sample tasks in T-maze. Adenovirus-mediated BDNF gene expression enhanced neuronal plasticity, as revealed by behavioral tests and LTP formation. Chronic administration of carnitine over time pre- and post-lesions seemed to partially ameliorate the cognitive deficits caused by the synaptic lesion. The carnitine-accelerated recovery from synaptic damage was observed by electron microscopy. These results demonstrate that the BoNTx-lesioned rat can be used as a model for dementia and that cognitive deficits can be alleviated in part by BDNF gene transfer or carnitine administration. Copyright 2002 Wiley-Liss, Inc.

Control of Spine Maturation and Pruning through ProBDNF Synthesized and Released in Dendrites

PubMed Central

Orefice, Lauren L.; Shih, Chien-Cheng; Xu, Haifei; Waterhouse, Emily G.; Xu, Baoji

2015-01-01

Excess synapses formed during early postnatal development are pruned over an extended period, while the remaining synapses mature. Synapse pruning is critical for activity-dependent refinement of neuronal connections and its dysregulation has been found in neurodevelopmental disorders such as autism spectrum disorders; however, the mechanism underlying synapse pruning remains largely unknown. As dendritic spines are the postsynaptic sites for the vast majority of excitatory synapses, spine maturation and pruning are indicators for maturation and elimination of these synapses. Our previous studies have found that dendritically localized mRNA for brain-derived neurotrophic factor (BDNF) regulates spine maturation and pruning. Here we investigated the mechanism by which dendritic Bdnf mRNA, but not somatically restricted Bdnf mRNA, promotes spine maturation and pruning. We found that neuronal activity stimulates both translation of dendritic Bdnf mRNA and secretion of its translation product mainly as proBDNF. The secreted proBDNF promotes spine maturation and pruning, and its effect on spine pruning is in part mediated by the p75NTR receptor via RhoA activation. Furthermore, some proBDNF is extracellularly converted to mature BDNF and then promotes maturation of stimulated spines by activating Rac1 through the TrkB receptor. In contrast, translation of somatic Bdnf mRNA and the release of its translation product mainly as mature BDNF are independent of action potentials. These results not only reveal a biochemical pathway regulating synapse pruning, but also suggest that BDNF synthesized in the soma and dendrites is released through distinct secretory pathways. PMID:26705735

Aerobic exercise upregulates the BDNF-Serotonin systems and improves the cognitive function in rats.

PubMed

Pietrelli, A; Matković, L; Vacotto, M; Lopez-Costa, J J; Basso, N; Brusco, A

2018-05-23

Aerobic exercise (AE) benefits brain health and behavior. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are known to mediate and shape cognitive processes. Both systems share some actions: BDNF is involved in the maturation and function of 5-HT neurons. In turn, 5-HT is involved in neuroplasticity phenomena mediated by BDNF and stimulated by exercise. The aim of this work was to study the long-term effects of AE on BDNF- 5-HT systems and cognitive function in rats at different ages. A lifelong moderate-intensity aerobic training program was designed, in which aerobically exercised (E) and sedentary control (C) rats were studied at middle (8 months) and old age (18 months) by means of biochemical, immunohistochemical and behavioral assays. The levels and expression of BDNF, 5-HT, serotonin transporter (SERT) and 5-HT 1A receptor were determined in selected brain areas involved in memory and learning. Immunopositive cells to neuronal nuclear protein (NeuN) in the hippocampus CA1 area were also quantified. The cognitive function was evaluated by the object recognition test (ORT). Results indicate that AE enhanced spatial and non-spatial memory systems, modulated by age. This outcome temporarily correlated with a significant upregulation of cortical, hippocampal and striatal BDNF levels in parallel with an increase in the number of hippocampal CA1-mature neurons. AE also increased brain and raphe 5-HT levels, as well as the expression of SERT and 5-HT 1A receptor in the cortex and hippocampus. Old AE rats showed a highly conserved response, indicating a remarkable protective effect of exercise on both systems. In summary, lifelong AE positively affects BDNF-5-HT systems, improves cognitive function and protects the brain against the deleterious effects of sedentary life and aging. Copyright © 2018 Elsevier Inc. All rights reserved.

Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB

PubMed Central

Dekeyster, Eline; Geeraerts, Emiel; Buyens, Tom; Van den Haute, Chris; Baekelandt, Veerle; De Groef, Lies; Salinas-Navarro, Manuel; Moons, Lieve

2015-01-01

According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce retinal ganglion cell (RGC) degeneration. Therefore, interfering with neurotrophic signaling seems an attractive strategy to achieve neuroprotection. Indeed, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs in animal models of glaucoma; however, the neuroprotective effect was mostly insufficient for sustained RGC survival. We hypothesized that treatment at the level of neurotrophin-releasing brain areas might be beneficial, as signaling pathways activated by target-derived neurotrophins are suggested to differ from pathways that are initiated at the soma membrane. In our study, first, the spatiotemporal course of RGC degeneration was characterized in mice subjected to optic nerve crush (ONC) or laser induced ocular hypertension (OHT). Subsequently, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule, and the levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the mouse retina and superior colliculus (SC) upon ONC and OHT. Both models differentially influenced BDNF and TrkB levels. Next, we aimed for RGC protection through viral vector-mediated upregulation of collicular BDNF, thought to boost the retrograde neurotrophin delivery. Although the previously reported temporary neuroprotective effect of intravitreally delivered recombinant BDNF was confirmed, viral vector-induced BDNF overexpression in the SC did not result in protection of the RGCs in the glaucoma models used. These findings most likely relate to decreased neurotrophin responsiveness upon vector-mediated BDNF overexpression. Our results highlight important insights concerning the complexity of neurotrophic factor treatments that should surely be considered in future

BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort

PubMed Central

Avgan, Nesli; Sutherland, Heidi G.; Spriggens, Lauren K.; Yu, Chieh; Ibrahim, Omar; Bellis, Claire; Haupt, Larisa M.; Shum, David H. K.; Griffiths, Lyn R.

2017-01-01

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory (p-value = 0.003) in a small cohort (n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale—Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism (p-value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF, and its anti-sense transcript BDNF-AS, in long-term visual memory performance. PMID:28304362

BDNF Variants May Modulate Long-Term Visual Memory Performance in a Healthy Cohort.

PubMed

Avgan, Nesli; Sutherland, Heidi G; Spriggens, Lauren K; Yu, Chieh; Ibrahim, Omar; Bellis, Claire; Haupt, Larisa M; Shum, David H K; Griffiths, Lyn R

2017-03-17

Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive functions including learning and memory. BDNF plays an important role in synaptic plasticity in humans and rats with BDNF shown to be essential for the formation of long-term memories. We previously identified a significant association between the BDNF Val66Met polymorphism (rs6265) and long-term visual memory ( p -value = 0.003) in a small cohort ( n = 181) comprised of healthy individuals who had been phenotyped for various aspects of memory function. In this study, we have extended the cohort to 597 individuals and examined multiple genetic variants across both the BDNF and BDNF-AS genes for association with visual memory performance as assessed by the Wechsler Memory Scale-Fourth Edition subtests Visual Reproduction I and II (VR I and II). VR I assesses immediate visual memory, whereas VR II assesses long-term visual memory. Genetic association analyses were performed for 34 single nucleotide polymorphisms genotyped on Illumina OmniExpress BeadChip arrays with the immediate and long-term visual memory phenotypes. While none of the BDNF and BDNF-AS variants were shown to be significant for immediate visual memory, we found 10 variants (including the Val66Met polymorphism ( p -value = 0.006)) that were nominally associated, and three variants (two variants in BDNF and one variant in the BDNF-AS locus) that were significantly associated with long-term visual memory. Our data therefore suggests a potential role for BDNF , and its anti-sense transcript BDNF-AS , in long-term visual memory performance.

Differential effects of BDNF and neurotrophin 4 (NT4) on endocytic sorting of TrkB receptors.

PubMed

Proenca, Catia C; Song, Minseok; Lee, Francis S

2016-08-01

Neurotrophins are a family of growth factors playing key roles in the survival, development, and function of neurons. The neurotrophins brain-derived neurotrophic factor (BDNF) and NT4 both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. The molecular mechanism of how TrkB activation by BDNF and NT4 leads to diverse outcomes is unknown. Here, we report that BDNF and NT4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions in cultured cortical neurons. Fluorescent microscopy and surface biotinylation experiments showed that both neurotrophins stimulate internalization of TrkB with similar kinetics. Exposure to BDNF for 2-3 h reduced the surface pool of TrkB receptors to half, whereas a longer treatment (4-5 h) with NT4 was necessary to achieve a similar level of down-regulation. Although BDNF and NT4 induced TrkB phosphorylation with similar intensities, BDNF induced more rapid ubiquitination and degradation of TrkB than NT4. Interestingly, TrkB receptor ubiquitination by these ligands have substantially different pH sensitivities, resulting in varying degrees of receptor ubiquitination at lower pH levels. Consequently, NT4 was capable of maintaining longer sustained downstream signaling activation that correlated with reduced TrkB ubiquitination at endosomal pH. Thus, by leading to altered endocytic trafficking itineraries for TrkB receptors, BDNF and NT4 elicit differential TrkB signaling in terms of duration, intensity, and specificity, which may contribute to their functional differences in vivo. The neurotrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), both bind to and activate TrkB receptors, however, they mediate distinct neuronal functions. Here, we propose that BDNF and NT4 lead to differential endocytic sorting of TrkB receptors resulting in diverse biological functions. BDNF induces more rapid ubiquitination and degradation of TrkB than NT4

Localization of BDNF expression in the developing brain of zebrafish.

PubMed

De Felice, E; Porreca, I; Alleva, E; De Girolamo, P; Ambrosino, C; Ciriaco, E; Germanà, A; Sordino, P

2014-05-01

The brain-derived neurotrophic factor (BDNF) gene is expressed in differentiating and post-mitotic neurons of the zebrafish embryo, where it has been implicated in Huntington's disease. Little is known, however, about the full complement of neuronal cell types that express BDNF in this important vertebrate model. Here, we further explored the transcriptional profiles during the first week of development using real-time quantitative polymerase chain reaction (RT-qPCR) and whole-mount in situ hybridization (WISH). RT-qPCR results revealed a high level of maternal contribution followed by a steady increase of zygotic transcription, consistent with the notion of a prominent role of BDNF in neuronal maturation and maintenance. Based on WISH, we demonstrate for the first time that BDNF expression in the developing brain of zebrafish is structure specific. Anatomical criteria and co-staining with genetic markers (shh, pax2a, emx1, krox20, lhx2b and lhx9) visualized major topological domains of BDNF-positive cells in the pallium, hypothalamus, posterior tuberculum and optic tectum. Moreover, the relative timing of BDNF transcription in the eye and tectum may illustrate a mechanism for coordinated development of the retinotectal system. Taken together, our results are compatible with a local delivery and early role of BDNF in the developing brain of zebrafish, adding basic knowledge to the study of neurotrophin functions in neural development and disease. © 2014 Anatomical Society.

Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD).

PubMed

Hemmings, Sîan M J; Kinnear, Craig J; Van der Merwe, Lize; Lochner, Christine; Corfield, Valerie A; Moolman-Smook, Johanna C; Stein, Dan J

2008-01-01

Although evidence from family studies suggest that genetic factors play an important role in mediating obsessive-compulsive disorder (OCD), results from genetic case-control association analyses have been inconsistent. Discrepant findings may be attributed to the lack of phenotypic resolution, and population stratification. The aim of the present study was to investigate the role that the val66met variant within the gene encoding brain-derived neurotrophic factor (BDNF) may play in mediating the development of selected OCD subtypes accounting for the aforementioned confounding factors. One hundred and twelve OCD subjects and 140 controls were selected from the South African Afrikaner population. A significant association was observed in the male subgroup, with the met66 allele implicated as the risk allele in the development of OCD. This allele was also found to be associated with an earlier age at onset of OCD in males. On the other hand, the val66val genotype was associated with more severe OCD in the female population. No evidence of population stratification was observed in Afrikaner control subjects. These preliminary results point towards genetically distinct characteristics of OCD mediated by dysfunctions in BDNF. The present investigation forms part of ongoing research to elucidate the genetic components involved in the aetiology of OCD and OCD-related characteristics.

Prenatal exposure to polycyclic aromatic hydrocarbons/aromatics, BDNF and child development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perera, Frederica, E-mail: fpp1@columbia.edu; Columbia Center for Children's Environmental Health, Columbia University, 722 W. 168th St., New York, NY 10032; Phillips, David H.

Objectives: Within a New York City (NYC) birth cohort, we assessed the associations between polycyclic aromatic hydrocarbon (PAH) and other aromatic DNA adducts and brain derived neurotrophic factor (BDNF) concentrations in umbilical cord blood, and neurodevelopment at age 2 years and whether BDNF is a mediator of the associations between PAH/aromatic-DNA adducts and neurodevelopment. Methods: PAH/aromatic-DNA adduct concentrations in cord blood were measured in 505 children born to nonsmoking African-American and Dominican women residing in NYC, and a subset was assessed for neurodevelopment at 2 years using the Bayley Scales of Infant Development Mental Development Index (MDI). A spectrum ofmore » PAH/aromatic-DNA adducts was measured using the {sup 32}P-postlabeling assay; DNA adducts formed by benzo[a]pyrene (B[a]P), a representative PAH, were measured by High Performance Liquid Chromatography (HPLC)/fluorescence. BDNF mature protein in cord blood plasma was quantified by an ELISA. Multivariate regression analysis, adjusting for potential confounders, was conducted. Results: PAH/aromatic-DNA adduct concentration measured by postlabeling was inversely associated with BDNF concentration (p=0.02) and with MDI scores at 2 years (p=0.04). BDNF level was positively associated with MDI scores (p=0.003). Restricting to subjects having all three measures (PAH/aromatic-DNA adducts by postlabeling, MDI, and BDNF), results were similar but attenuated (p=0.13, p=0.05, p=0.01, respectively). Associations between B[a]P-DNA adducts and BDNF and B[a]P-DNA adducts and MDI at age 2 years were not significant. At age 3 years, the positive association of BDNF with MDI was not observed. Conclusions: The results at age 2 suggest that prenatal exposure to a spectrum of PAH/aromatic pollutants may adversely affect early neurodevelopment, in part by reducing BDNF levels during the fetal period. However, the same relationship was not seen at age 3. - Highlights: • Cord blood

Prolonged maternal separation attenuates BDNF-ERK signaling correlated with spine formation in the hippocampus during early brain development.

PubMed

Ohta, Ken-Ichi; Suzuki, Shingo; Warita, Katsuhiko; Kaji, Tomohiro; Kusaka, Takashi; Miki, Takanori

2017-04-01

Maternal separation (MS) is known to affect hippocampal function such as learning and memory, yet the molecular mechanism remains unknown. We hypothesized that these impairments are attributed to abnormities of neural circuit formation by MS, and focused on brain-derived neurotrophic factor (BDNF) as key factor because BDNF signaling has an essential role in synapse formation during early brain development. Using rat offspring exposed to MS for 6 h/day during postnatal days (PD) 2-20, we estimated BDNF signaling in the hippocampus during brain development. Our results show that MS attenuated BDNF expression and activation of extracellular signal-regulated kinase (ERK) around PD 7. Moreover, plasticity-related immediate early genes, which are transcriptionally regulated by BDNF-ERK signaling, were also reduced by MS around PD 7. Interestingly, detailed analysis revealed that MS particularly reduced expression of BDNF gene and immediate early genes in the cornu ammonis 1 (CA1) of hippocampus at PD 7. Considering that BDNF-ERK signaling is involved in spine formation, we next evaluated spine formation in the hippocampus during the weaning period. Our results show that MS particularly reduced mature spine density in proximal apical dendrites of CA1 pyramidal neurons at PD 21. These results suggest that MS could attenuate BDNF-ERK signaling during primary synaptogenesis with a region-specific manner, which is likely to lead to decreased spine formation and maturation observed in the hippocampal CA1 region. It is speculated that this incomplete spine formation during early brain development has an influence on learning capabilities throughout adulthood. © 2017 International Society for Neurochemistry.

IL-1β impairs retrograde flow of BDNF signaling by attenuating endosome trafficking.

PubMed

Carlos, Anthony J; Tong, Liqi; Prieto, G Aleph; Cotman, Carl W

2017-02-02

Pro-inflammatory cytokines accumulate in the brain with age and Alzheimer's disease and can impair neuron health and cognitive function. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin that supports neuron health, function, and synaptic plasticity. The pro-inflammatory cytokine interleukin-1β (IL-1β) impairs BDNF signaling but whether it affects BDNF signaling endosome trafficking has not been studied. This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL-1β on BDNF signaling endosome trafficking. Neurons were cultured in microfluidic chambers that separate the environments of the cell body and its axon terminal, enabling us to specifically treat in axon compartments and trace vesicle trafficking in real-time. We found that IL-1β attenuates BDNF signaling endosomes throughout networks in cultures. In IL-1β-treated cells, overall BDNF endosomal density was decreased, and the colocalization of BDNF endosomes with presynaptic terminals was found to be more than two times higher than in control cultures. Selective IL-1β treatment to the presynaptic compartment in microfluidic chamber attenuated BDNF endosome flux, as measured by reduced BDNF-GFP endosome counts in the somal compartment. Further, IL-1β decreased the BDNF-induced phosphorylation of Erk5, a known BDNF retrograde trafficking target. Mechanistically, the deficiency in trafficking was not due to impaired endocytosis of the BDNF-TrkB complex, or impaired transport rate, since BDNF endosomes traveled at the same rate in both control and IL-1β treatment groups. Among the regulators of presynaptic endosome sorting is the post-translational modification, ubiquitination. In support of this possibility, the IL-1β-mediated suppression of BDNF-induced Erk5 phosphorylation can be rescued by exogenous ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that regulates ubiquitin and endosomal trafficking. We observed a state of

Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults - A randomized controlled trial.

PubMed

Hvid, L G; Nielsen, M K F; Simonsen, C; Andersen, M; Caserotti, P

2017-07-01

Brain-derived neurotrophic factor (BDNF) is a potential important factor involved in neuroplasticity, and may be a mediator for eliciting adaptations in neuromuscular function and physical function in older individuals following physical training. As power training taxes the neural system to a very high extent, it may be particularly effective in terms of eliciting increases in systemic BDNF levels. We examined the effects of 12weeks of power training on mature BDNF (mBDNF) and total BDNF (tBDNF) in mobility-limited older adults from the Healthy Ageing Network of Competence (HANC) study. We included 47 older men and women: n=22 in the training group (TG: progressive high intensity power training, 2 sessions per week; age 82.7±5.4years, 55% women) and n=25 in the control group (CG: no interventions; age 82.2±4.5years, 76% women). Following overnight fasting, basal serum levels of mBDNF and tBDNF were assessed (human ELISA kits) at baseline and post-intervention. At baseline, mBDNF and tBDNF levels were comparable in the two groups, TG and CG. Post-intervention, no significant within-group or between-group changes were observed in mBDNF or tBDNF. Moreover, when divided into responder tertiles based upon changes in mBDNF and tBDNF (i.e. decliners, maintainers, improvers), respectively, comparable findings were observed for TG and CG. Altogether, basal systemic levels of serum mBDNF and tBDNF are not affected in mobility-limited older adults following 12-weeks of power training, and do not appear to be a major mechanistic factor mediating neuroplasticity in mobility-limited older adults. Copyright © 2017 Elsevier Inc. All rights reserved.

Ubiquilin/Dsk2 promotes inclusion body formation and vacuole (lysosome)-mediated disposal of mutated huntingtin.

PubMed

Chuang, Kun-Han; Liang, Fengshan; Higgins, Ryan; Wang, Yanchang

2016-07-01

Ubiquilin proteins contain a ubiquitin-like domain (UBL) and ubiquitin-associated domain(s) that interact with the proteasome and ubiquitinated substrates, respectively. Previous work established the link between ubiquilin mutations and neurodegenerative diseases, but the function of ubiquilin proteins remains elusive. Here we used a misfolded huntingtin exon I containing a 103-polyglutamine expansion (Htt103QP) as a model substrate for the functional study of ubiquilin proteins. We found that yeast ubiquilin mutant (dsk2Δ) is sensitive to Htt103QP overexpression and has a defect in the formation of Htt103QP inclusion bodies. Our evidence further suggests that the UBL domain of Dsk2 is critical for inclusion body formation. Of interest, Dsk2 is dispensable for Htt103QP degradation when Htt103QP is induced for a short time before noticeable inclusion body formation. However, when the inclusion body forms after a long Htt103QP induction, Dsk2 is required for efficient Htt103QP clearance, as well as for autophagy-dependent delivery of Htt103QP into vacuoles (lysosomes). Therefore our data indicate that Dsk2 facilitates vacuole-mediated clearance of misfolded proteins by promoting inclusion body formation. Of importance, the defect of inclusion body formation in dsk2 mutants can be rescued by human ubiquilin 1 or 2, suggesting functional conservation of ubiquilin proteins. © 2016 Chuang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice.

PubMed

Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L; Lee, Francis S; Blendy, Julie A

2015-12-01

Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal. Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For

A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS.

PubMed

Cheeran, Binith; Talelli, Penelope; Mori, Francesco; Koch, Giacomo; Suppa, Antonio; Edwards, Mark; Houlden, Henry; Bhatia, Kailash; Greenwood, Richard; Rothwell, John C

2008-12-01

The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non-invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

Association between BDNF-rs6265 and obesity in the Boston Puerto Rican Health Study

USDA-ARS?s Scientific Manuscript database

The objective of this study is to examine a functional variant (rs6265) in the BDNF gene interacting with dietary intake modulate obesity traits in the Boston Puerto Rican Health Study population. BDNF rs6265 was genotyped in 1147 Puerto Ricans (aged 45-75 years), and examined for association with o...

ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions.

PubMed

Je, H Shawn; Yang, Feng; Ji, Yuanyuan; Potluri, Srilatha; Fu, Xiu-Qing; Luo, Zhen-Ge; Nagappan, Guhan; Chan, Jia Pei; Hempstead, Barbara; Son, Young-Jin; Lu, Bai

2013-06-12

During development, mammalian neuromuscular junctions (NMJs) transit from multiple-innervation to single-innervation through axonal competition via unknown molecular mechanisms. Previously, using an in vitro model system, we demonstrated that the postsynaptic secretion of pro-brain-derived neurotrophic factor (proBDNF) stabilizes or eliminates presynaptic axon terminals, depending on its proteolytic conversion at synapses. Here, using developing mouse NMJs, we obtained in vivo evidence that proBDNF and mature BDNF (mBDNF) play roles in synapse elimination. We observed that exogenous proBDNF promoted synapse elimination, whereas mBDNF infusion substantially delayed synapse elimination. In addition, pharmacological inhibition of the proteolytic conversion of proBDNF to mBDNF accelerated synapse elimination via activation of p75 neurotrophin receptor (p75(NTR)). Furthermore, the inhibition of both p75(NTR) and sortilin signaling attenuated synapse elimination. We propose a model in which proBDNF and mBDNF serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, in vivo.

Roles of p62 in BDNF-dependent autophagy suppression and neuroprotection against mitochondrial dysfunction in rat cortical neurons.

PubMed

Wu, Chia-Lin; Chen, Chien-Hui; Hwang, Chi-Shin; Chen, Shang-Der; Hwang, Wei-Chao; Yang, Ding-I

2017-03-01

Previously, we have reported that pre-conditioning of primary rat cortical neurons with brain-derived neurotrophic factor (BDNF) may exert neuroprotective effects against 3-nitropropionic acid (3-NP), a mitochondrial complex II inhibitor. However, the underlying mechanisms, especially potential involvements of autophagy, remain elusive. In this work, we tested the hypothesis that BDNF may suppress 3-NP-induced autophagy to exert its neuroprotective effects by inducing the expression of p62/sequestosome-1 in primary cortical neurons. We found that 3-NP increased total level of microtubule-associated protein 1A/1B-light chain (LC)-3 as well as the LC3-II/LC3-I ratio, an index of autophagy, in primary cortical neurons. BDNF decreased LC3-II/LC3-I ratio and time-dependently induced expression of p62. Knockdown of p62 by siRNA restored LC3-II/LC3-I ratio and increased total LC3 levels associated with BDNF exposure; p62 knockdown also abolished BDNF-dependent neuroprotection against 3-NP. Upstream of p62, we found that BDNF triggered phosphorylation of mammalian target of rapamycin (mTOR) and its downstream mediator p70S6K; importantly, the mTOR inhibitor rapamycin reduced both BDNF-dependent p62 induction as well as 3-NP resistance. BDNF is known to induce c-Jun in cortical neurons. We found that c-Jun knockdown in part attenuated BDNF-mediated p62 induction, whereas p62 knockdown had no significant effects on c-Jun expression. In addition to suppressing p62 induction, rapamycin also partially suppressed BDNF-induced c-Jun expression, but c-Jun knockdown failed to affect mTOR activation. Together, our results suggested that BDNF inhibits 3-NP-induced autophagy via, at least in part, mTOR/c-Jun-dependent induction of p62 expression, together contributing to neuroprotection against mitochondrial inhibition. © 2016 International Society for Neurochemistry.

The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Qiujun; Department of Anesthesiology, The Third Clinical Hospital, Hebei Medical University, Shijiazhuang, Hebei 050051; Liang Ge

2011-02-01

Isoflurane is known to increase {beta}-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh{sup Q111/Q111}) and wild type (STHdh{sup Q7/Q7}) striatal neurons. The primary cultured neurons were exposed for 24 h to equipotent concentrations of isoflurane, sevoflurane, and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP{sub 3}) receptor antagonist. Aggregation of huntingtin protein, cellmore » viability, and calcium concentrations were measured. Isoflurane, sevoflurane, and desflurane all increased the aggregation of huntingtin in STHdh{sup Q111/Q111} cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdh{sup Q111/Q111} huntingtin cells than in the wild type STHdh{sup Q7/Q7} striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh{sup Q111/Q111} cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP{sub 3} receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh{sup Q111/Q111} striatal cells.« less

Propofol alleviates electroconvulsive shock-induced memory impairment by modulating proBDNF/mBDNF ratio in depressive rats.

PubMed

Zhang, Fan; Luo, Jie; Min, Su; Ren, Li; Qin, Peipei

2016-07-01

This study investigated the effects of propofol and electroconvulsive shock (ECS), the analogue of electroconvulsive therapy (ECT) in animals, on tissue plasminogen activator (tPA) and its inhibitor (PAI-1) as well as the precursor of brain-derived neurotrophic factor (proBDNF)/mature BDNF (mBDNF) ratio in depressive rats. ECT is an effective treatment for depression, but can cause cognitive deficit. Some studies have indicated that propofol can ameliorate cognitive decline induced by ECT, but the underlying molecular mechanism is still unclear. Recent evidence has found that mBDNF and its precursor proBDNF are related to depression and cognitive function; they elicit opposite effects on cellular functions. Chronic unpredicted mild stress is widely used to induce depressive behaviors in rodents. This study found that the depression resulted in an increased expression of PAI-1 and upregulation of the proBDNF/mBDNF ratio, together with a decreased level of tPA, long-term potentiation (LTP) impairment, and cognitive decline. The proBDNF/mBDNF ratio was further upregulated after the ECS treatment in depressive rats, resulting in the deterioration of cognitive function and hippocampal LTP. Propofol alone did not reverse the changes in depressive rats, but when co-administered with ECS, it improved the cognitive function, alleviated the impairment of LTP, downregulated the proBDNF/mBDNF ratio, and increased the tPA expression. The results of this study suggest that propofol ameliorates cognitive decline induced by ECT, which was partly by modulating the proBDNF/mBDNF ratio and reversing the excessive changes in hippocampal synaptic plasticity, providing a new evidence for involving the proBDNF/mBDNF system in the progression and treatment of depression. Copyright © 2016 Elsevier B.V. All rights reserved.

Activity-Dependent Human Brain Coding/Noncoding Gene Regulatory Networks

PubMed Central

Lipovich, Leonard; Dachet, Fabien; Cai, Juan; Bagla, Shruti; Balan, Karina; Jia, Hui; Loeb, Jeffrey A.

2012-01-01

While most gene transcription yields RNA transcripts that code for proteins, a sizable proportion of the genome generates RNA transcripts that do not code for proteins, but may have important regulatory functions. The brain-derived neurotrophic factor (BDNF) gene, a key regulator of neuronal activity, is overlapped by a primate-specific, antisense long noncoding RNA (lncRNA) called BDNFOS. We demonstrate reciprocal patterns of BDNF and BDNFOS transcription in highly active regions of human neocortex removed as a treatment for intractable seizures. A genome-wide analysis of activity-dependent coding and noncoding human transcription using a custom lncRNA microarray identified 1288 differentially expressed lncRNAs, of which 26 had expression profiles that matched activity-dependent coding genes and an additional 8 were adjacent to or overlapping with differentially expressed protein-coding genes. The functions of most of these protein-coding partner genes, such as ARC, include long-term potentiation, synaptic activity, and memory. The nuclear lncRNAs NEAT1, MALAT1, and RPPH1, composing an RNAse P-dependent lncRNA-maturation pathway, were also upregulated. As a means to replicate human neuronal activity, repeated depolarization of SY5Y cells resulted in sustained CREB activation and produced an inverse pattern of BDNF-BDNFOS co-expression that was not achieved with a single depolarization. RNAi-mediated knockdown of BDNFOS in human SY5Y cells increased BDNF expression, suggesting that BDNFOS directly downregulates BDNF. Temporal expression patterns of other lncRNA-messenger RNA pairs validated the effect of chronic neuronal activity on the transcriptome and implied various lncRNA regulatory mechanisms. lncRNAs, some of which are unique to primates, thus appear to have potentially important regulatory roles in activity-dependent human brain plasticity. PMID:22960213

Spontaneous sleep-wake cycle and sleep deprivation differently induce Bdnf1, Bdnf4 and Bdnf9a DNA methylation and transcripts levels in the basal forebrain and frontal cortex in rats.

PubMed

Ventskovska, Olena; Porkka-Heiskanen, Tarja; Karpova, Nina N

2015-04-01

Brain-derived neurotrophic factor (Bdnf) regulates neuronal plasticity, slow wave activity and sleep homeostasis. Environmental stimuli control Bdnf expression through epigenetic mechanisms, but there are no data on epigenetic regulation of Bdnf by sleep or sleep deprivation. Here we investigated whether 5-methylcytosine (5mC) DNA modification at Bdnf promoters p1, p4 and p9 influences Bdnf1, Bdnf4 and Bdnf9a expression during the normal inactive phase or after sleep deprivation (SD) (3, 6 and 12 h, end-times being ZT3, ZT6 and ZT12) in rats in two brain areas involved in sleep regulation, the basal forebrain and cortex. We found a daytime variation in cortical Bdnf expression: Bdnf1 expression was highest at ZT6 and Bdnf4 lowest at ZT12. Such variation was not observed in the basal forebrain. Also Bdnf p1 and p9 methylation levels differed only in the cortex, while Bdnf p4 methylation did not vary in either area. Factorial analysis revealed that sleep deprivation significantly induced Bdnf1 and Bdnf4 with the similar pattern for Bdnf9a in both basal forebrain and cortex; 12 h of sleep deprivation decreased 5mC levels at the cortical Bdnf p4 and p9. Regression analysis between the 5mC promoter levels and the corresponding Bdnf transcript expression revealed significant negative correlations for the basal forebrain Bdnf1 and cortical Bdnf9a transcripts in only non-deprived rats, while these correlations were lost after sleep deprivation. Our results suggest that Bdnf transcription during the light phase of undisturbed sleep-wake cycle but not after SD is regulated at least partially by brain site-specific DNA methylation. © 2014 European Sleep Research Society.

Peripheral vascular reactivity and serum BDNF responses to aerobic training are impaired by the BDNF Val66Met polymorphism.

PubMed

Lemos, José R; Alves, Cleber R; de Souza, Sílvia B C; Marsiglia, Julia D C; Silva, Michelle S M; Pereira, Alexandre C; Teixeira, Antônio L; Vieira, Erica L M; Krieger, José E; Negrão, Carlos E; Alves, Guilherme B; de Oliveira, Edilamar M; Bolani, Wladimir; Dias, Rodrigo G; Trombetta, Ivani C

2016-02-01

Besides neuronal plasticity, the neurotrophin brain-derived neurotrophic factor (BDNF) is also important in vascular function. The BDNF has been associated with angiogenesis through its specific receptor tropomyosin-related kinase B (TrkB). Additionally, Val66Met polymorphism decreases activity-induced BDNF. Since BDNF and TrkB are expressed in vascular endothelial cells and aerobic exercise training can increase serum BDNF, this study aimed to test the hypotheses: 1) Serum BDNF levels modulate peripheral blood flow; 2) The Val66Met BDNF polymorphism impairs exercise training-induced vasodilation. We genotyped 304 healthy male volunteers (Val66Val, n = 221; Val66Met, n = 83) who underwent intense aerobic exercise training on a running track three times/wk for 4 mo. We evaluated pre- and post-exercise training serum BDNF and proBDNF concentration, heart rate (HR), mean blood pressure (MBP), forearm blood flow (FBF), and forearm vascular resistance (FVR). In the pre-exercise training, BDNF, proBDNF, BDNF/proBDNF ratio, FBF, and FVR were similar between genotypes. After exercise training, functional capacity (V̇o2 peak) increased and HR decreased similarly in both groups. Val66Val, but not Val66Met, increased BDNF (interaction, P = 0.04) and BDNF/proBDNF ratio (interaction, P < 0.001). Interestingly, FBF (interaction, P = 0.04) and the FVR (interaction, P = 0.01) responses during handgrip exercise (HG) improved in Val66Val compared with Val66Met, even with similar responses of HR and MBP. There were association between BDNF/proBDNF ratio and FBF (r = 0.64, P < 0.001) and FVR (r = -0.58, P < 0.001) during HG exercise. These results show that peripheral vascular reactivity and serum BDNF responses to exercise training are impaired by the BDNF Val66Met polymorphism and such responsiveness is associated with serum BDNF concentrations in healthy subjects. Copyright © 2016 the American Physiological Society.

BDNF is required for taste axon regeneration following unilateral chorda tympani nerve section.

PubMed

Meng, Lingbin; Huang, Tao; Sun, Chengsan; Hill, David L; Krimm, Robin

2017-07-01

Taste nerves readily regenerate to reinnervate denervated taste buds; however, factors required for regeneration have not yet been identified. When the chorda tympani nerve is sectioned, expression of brain-derived neurotrophic factor (BDNF) remains high in the geniculate ganglion and lingual epithelium, despite the loss of taste buds. These observations suggest that BDNF is present in the taste system after nerve section and may support taste nerve regeneration. To test this hypothesis, we inducibly deleted Bdnf during adulthood in mice. Shortly after Bdnf gene recombination, the chorda tympani nerve was unilaterally sectioned causing a loss of both taste buds and neurons, irrespective of BDNF levels. Eight weeks after nerve section, however, regeneration was differentially affected by Bdnf deletion. In control mice, there was regeneration of the chorda tympani nerve and taste buds reappeared with innervation. In contrast, few taste buds were reinnervated in mice lacking normal Bdnf expression such that taste bud number remained low. In all genotypes, taste buds that were reinnervated were normal-sized, but non-innervated taste buds remained small and atrophic. On the side of the tongue contralateral to the nerve section, taste buds for some genotypes became larger and all taste buds remained innervated. Our findings suggest that BDNF is required for nerve regeneration following gustatory nerve section. Copyright © 2017 Elsevier Inc. All rights reserved.

Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

PubMed Central

Malikova, Jana; Camats, Núria; Fernández-Cancio, Mónica; Heath, Karen; González, Isabel; Caimarí, María; del Campo, Miguel; Albisu, Marian; Kolouskova, Stanislava; Audí, Laura; Flück, Christa E.

2014-01-01

Context Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. Objective To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. Patients 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. Methods SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Results Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Conclusions Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations. PMID:25122490

Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis.

PubMed

Malikova, Jana; Camats, Núria; Fernández-Cancio, Mónica; Heath, Karen; González, Isabel; Caimarí, María; del Campo, Miguel; Albisu, Marian; Kolouskova, Stanislava; Audí, Laura; Flück, Christa E

2014-01-01

Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation.

PubMed

Jarome, Timothy J; Butler, Anderson A; Nichols, Jessica N; Pacheco, Natasha L; Lubin, Farah D

2015-01-01

Gadd45-mediated DNA demethylation mechanisms have been implicated in the process of memory formation. However, the transcriptional mechanisms involved in the regulation of Gadd45 gene expression during memory formation remain unexplored. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) controls transcription of genes in neurons and is a critical regulator of synaptic plasticity and memory formation. In silico analysis revealed several NF-κB (p65/RelA and cRel) consensus sequences within the Gadd45β gene promoter. Whether NF-κB activity regulates Gadd45 expression and associated DNA demethylation in neurons during memory formation is unknown. Here, we found that learning in a fear conditioning paradigm increased Gadd45β gene expression and brain-derivedneurotrophic factor (BDNF) DNA demethylation in area CA1 of the hippocampus, both of which were prevented with pharmacological inhibition of NF-κB activity. Further experiments found that conditional mutations in p65/RelA impaired fear memory formation but did not alter changes in Gadd45β expression. The learning-induced increases in Gadd45β mRNA levels, Gadd45β binding at the BDNF gene and BDNF DNA demethylation were blocked in area CA1 of the c-rel knockout mice. Additionally, local siRNA-mediated knockdown of c-rel in area CA1 prevented fear conditioning-induced increases in Gadd45β expression and BDNF DNA demethylation, suggesting that c-Rel containing NF-κB transcription factor complex is responsible for Gadd45β regulation during memory formation. Together, these results support a novel transcriptional role for NF-κB in regulation of Gadd45β expression and DNA demethylation in hippocampal neurons during fear memory.

[Study of genetic variants in the BDNF, COMT, DAT1 and SERT genes in Colombian children with attention deficit disorder].

PubMed

Ortega-Rojas, Jenny; Arboleda-Bustos, Carlos E; Morales, Luis; Benítez, Bruno A; Beltrán, Diana; Izquierdo, Álvaro; Arboleda, Humberto; Vásquez, Rafael

Attention deficit and hyperactive disorder (ADHD) is highly prevalent among children in Bogota City. Both genetic and environmental factors play a very important role in the etiology of ADHD. However, to date few studies have addressed the association of genetic variants and ADHD in the Colombian population. To test the genetic association between polymorphisms in the DAT1, HTTLPR, COMT and BDNF genes and ADHD in a sample from Bogota City. We genotyped the most common polymorphisms in DAT1, SERT, COMT and BDNF genes associated with ADHD using conventional PCR followed by restriction fragment length polymorphism (RFLP) in 97 trios recruited in a medical center in Bogota. The transmission disequilibrium test (TDT) was used to determine the association between such genetic variants and ADHD. The TDT analysis showed that no individual allele of any variant studied has a preferential transmission. Our results suggest that the etiology of the ADHD may be complex and involves several genetic factors. Further studies in other candidate polymorphisms in a larger sample size will improve our knowledge of the ADHD in Colombian population. Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Effect of brain-derived neurotrophic factor (BDNF) on hepatocyte metabolism.

PubMed

Genzer, Yoni; Chapnik, Nava; Froy, Oren

2017-07-01

Brain-derived neurotrophic factor (BDNF) plays crucial roles in the development, maintenance, plasticity and homeostasis of the central and peripheral nervous systems. Perturbing BDNF signaling in mouse brain results in hyperphagia, obesity, hyperinsulinemia and hyperglycemia. Currently, little is known whether BDNF affects liver tissue directly. Our aim was to determine the metabolic signaling pathways activated after BDNF treatment in hepatocytes. Unlike its effect in the brain, BDNF did not lead to activation of the liver AKT pathway. However, AMP protein activated kinase (AMPK) was ∼3 times more active and fatty acid synthase (FAS) ∼2-fold less active, suggesting increased fatty acid oxidation and reduced fatty acid synthesis. In addition, cAMP response element binding protein (CREB) was ∼3.5-fold less active together with its output the gluconeogenic transcript phosphoenolpyruvate carboxykinase (Pepck), suggesting reduced gluconeogenesis. The levels of glycogen synthase kinase 3b (GSK3b) was ∼3-fold higher suggesting increased glycogen synthesis. In parallel, the expression levels of the clock genes Bmal1 and Cry1, whose protein products play also a metabolic role, were ∼2-fold increased and decreased, respectively. In conclusion, BDNF binding to hepatocytes leads to activation of catabolic pathways, such as fatty acid oxidation. In parallel gluconeogenesis is inhibited, while glycogen storage is triggered. This metabolic state mimics that of after breakfast, in which the liver continues to oxidize fat, stops gluconeogenesis and replenishes glycogen stores. Copyright © 2017 Elsevier Ltd. All rights reserved.

Proteolytic Cleavage of ProBDNF into Mature BDNF in the Basolateral Amygdala Is Necessary for Defeat-Induced Social Avoidance

ERIC Educational Resources Information Center

Dulka, Brooke N.; Ford, Ellen C.; Lee, Melissa A.; Donnell, Nathaniel J.; Goode, Travis D.; Prosser, Rebecca; Cooper, Matthew A.

2016-01-01

Brain-derived neurotrophic factor (BDNF) is essential for memory processes. The present study tested whether proteolytic cleavage of proBDNF into mature BDNF (mBDNF) within the basolateral amygdala (BLA) regulates the consolidation of defeat-related memories. We found that acute social defeat increases the expression of mBDNF, but not proBDNF, in…

Pharmacological profile of brain-derived neurotrophic factor (BDNF) splice variant translation using a novel drug screening assay: a "quantitative code".

PubMed

Vaghi, Valentina; Polacchini, Alessio; Baj, Gabriele; Pinheiro, Vera L M; Vicario, Annalisa; Tongiorgi, Enrico

2014-10-03

The neurotrophin brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal development and plasticity. BDNF is a major pharmaceutical target in neurodevelopmental and psychiatric disorders. However, pharmacological modulation of this neurotrophin is challenging because BDNF is generated by multiple, alternatively spliced transcripts with different 5'- and 3'UTRs. Each BDNF mRNA variant is transcribed independently, but translation regulation is unknown. To evaluate the translatability of BDNF transcripts, we developed an in vitro luciferase assay in human neuroblastoma cells. In unstimulated cells, each BDNF 5'- and 3'UTR determined a different basal translation level of the luciferase reporter gene. However, constructs with either a 5'UTR or a 3'UTR alone showed poor translation modulation by BDNF, KCl, dihydroxyphenylglycine, AMPA, NMDA, dopamine, acetylcholine, norepinephrine, or serotonin. Constructs consisting of the luciferase reporter gene flanked by the 5'UTR of one of the most abundant BDNF transcripts in the brain (exons 1, 2c, 4, and 6) and the long 3'UTR responded selectively to stimulation with the different receptor agonists, and only transcripts 2c and 6 were increased by the antidepressants desipramine and mirtazapine. We propose that BDNF mRNA variants represent "a quantitative code" for regulated expression of the protein. Thus, to discriminate the efficacy of drugs in stimulating BDNF synthesis, it is appropriate to use variant-specific in vitro screening tests. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

HBpF-proBDNF: A New Tool for the Analysis of Pro-Brain Derived Neurotrophic Factor Receptor Signaling and Cell Biology.

PubMed

Gaub, Perrine; de Léon, Andrès; Gibon, Julien; Soubannier, Vincent; Dorval, Geneviève; Séguéla, Philippe; Barker, Philip A

2016-01-01

Neurotrophins activate intracellular signaling pathways necessary for neuronal survival, growth and apoptosis. The most abundant neurotrophin in the adult brain, brain-derived neurotrophic factor (BDNF), is first synthesized as a proBDNF precursor and recent studies have demonstrated that proBDNF can be secreted and that it functions as a ligand for a receptor complex containing p75NTR and sortilin. Activation of proBDNF receptors mediates growth cone collapse, reduces synaptic activity, and facilitates developmental apoptosis of motoneurons but the precise signaling cascades have been difficult to discern. To address this, we have engineered, expressed and purified HBpF-proBDNF, an expression construct containing a 6X-HIS tag, a biotin acceptor peptide (BAP) sequence, a PreScission™ Protease cleavage site and a FLAG-tag attached to the N-terminal part of murine proBDNF. Intact HBpF-proBDNF has activities indistinguishable from its wild-type counterpart and can be used to purify proBDNF signaling complexes or to monitor proBDNF endocytosis and retrograde transport. HBpF-proBDNF will be useful for characterizing proBDNF signaling complexes and for deciphering the role of proBDNF in neuronal development, synapse function and neurodegenerative disease.

The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex

PubMed Central

Pattwell, Siobhan S.; Bath, Kevin G.; Perez-Castro, Rosalia; Lee, Francis S.; Chao, Moses V.; Ninan, Ipe

2012-01-01

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNFMet carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNFMet/Met mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in N-methyl-D-aspartic acid (NMDA) and γ-aminobutyric acid (GABA) receptor-mediated synaptic transmission in the pyramidal neurons of BDNFMet/Met mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNFMet/Met mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNFMet/Met neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNFMet/Met mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this SNP's impact on affective disorders and cognitive dysfunction. PMID:22396415

Altering BDNF expression by genetics and/or environment: impact for emotional and depression-like behaviour in laboratory mice.

PubMed

Chourbaji, Sabine; Brandwein, Christiane; Gass, Peter

2011-01-01

According to the "neurotrophin hypothesis", brain-derived neurotrophic factor (BDNF) is an important candidate gene in depression. Moreover, environmental stress is known to represent a risk factor in the pathophysiology and treatment of this disease. To elucidate, whether changes of BDNF availability signify cause or consequence of depressive-like alterations, it is essential to look for endophenotypes under distinct genetic conditions (e.g. altered BDNF expression). Furthermore it is crucial to examine environment-driven BDNF regulation and its effect on depressive-linked features. Consequently, gene × environment studies investigating prospective genetic mouse models of depression in different environmental contexts become increasingly important. The present review summarizes recent findings in BDNF-mutant mice, which have been controversially discussed as models of depression and anxiety. It furthermore illustrates the potential of environment to serve as naturalistic stressor with the potential to modulate the phenotype in wildtype and mutant mice. Moreover, environment may exert protective effects by regulating BDNF levels as attributed to "environmental enrichment". The effect of this beneficial condition will also be discussed with regard to probable "curative/therapeutic" approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

Fear extinction and BDNF: Translating animal models of PTSD to the clinic

PubMed Central

Andero, Raül; Ressler, Kerry J

2012-01-01

Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity TrkB receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories, including fear memories. Among the psychiatric disorders with altered fear processing there is Post-traumatic Stress Disorder (PTSD) which is characterized by an inability to extinguish fear memories. Since BDNF appears to enhance extinction of fear, targeting impaired extinction in anxiety disorders such as PTSD via BDNF signalling may be an important and novel way to enhance treatment efficacy. The aim of this review is to provide a translational point of view that stems from findings in the BDNF regulation of synaptic plasticity and fear extinction. In addition, there are different systems that seem to alter fear extinction through BDNF modulation like the endocannabionoid system and the hypothalamic-pituitary adrenal axis (HPA). Recent work also finds that the pituitary adenylate cyclase-activating polypeptide (PACAP) and PAC1 receptor, which are upstream of BDNF activation, may be implicated in PTSD. Especially interesting are data that exogenous fear extinction enhancers such as antidepressants, histone deacetylases inhibitors (HDACi) and D-cycloserine, a partial NMDA agonist, may act through or in concert with the BDNF-TrkB system. Finally, we review studies where recombinant BDNF and a putative TrkB agonist, 7,8-DHF, may enhance extinction of fear. These approaches may lead to novel agents that improve extinction in animal models and eventually humans. PMID:22530815

Changes in Expression of Dopamine, Its Receptor, and Transporter in Nucleus Accumbens of Heroin-Addicted Rats with Brain-Derived Neurotrophic Factor (BDNF) Overexpression.

PubMed

Li, Yixin; Xia, Baijuan; Li, Rongrong; Yin, Dan; Liang, Wenmei

2017-06-09

BACKGROUND The aim of this study was to explore how changes in the expression of BDNF in MLDS change the effect of BDNF on dopamine (DA) neurons, which may have therapeutic implications for heroin addiction. MATERIAL AND METHODS We established a rat model of heroin addiction and observed changes in the expression of BDNF, DA, dopamine receptor (DRD), dopamine transporter (DAT), and other relevant pathways in NAc. We also assessed the effect of BDNF overexpression in the NAc, behavioral changes of heroin-conditioned place preference (CPP), and naloxone withdrawal in rats with high levels of BDNF. We established 5 adult male rat groups: heroin addiction, lentivirus transfection, blank virus, sham operation, and control. The PCR gene chip was used to study gene expression changes. BDNF lentivirus transfection was used for BDNF overexpression. A heroin CPP model and a naloxone withdrawal model of rats were established. RESULTS Expression changes were found in 20 of the 84 DA-associated genes in the NAc of heroin-addicted rats. Weight loss and withdrawal symptoms in the lentivirus group for naloxone withdrawal was less than in the blank virus and the sham operation group. These 2 latter groups also showed significant behavioral changes, but such changes were not observed in the BDNF lentivirus group before or after training. DRD3 and DAT increased in the NAc of the lentivirus group. CONCLUSIONS BDNF and DA in the NAc are involved in heroin addiction. BDNF overexpression in NAc reduces withdrawal symptoms and craving behavior for medicine induced by environmental cues for heroin-addicted rats. BDNF participates in the regulation of the dopamine system by acting on DRD3 and DAT.

The Role of BDNF Genotype, Parental Depression, and Relationship Discord in Predicting Early-Emerging Negative Emotionality

PubMed Central

Hayden, Elizabeth P.; Klein, Daniel N.; Dougherty, Lea R.; Olino, Thomas M.; Dyson, Margaret W.; Durbin, C. Emily; Sheikh, Haroon I.; Singh, Shiva M.

2012-01-01

The brain-derived neurotrophic factor (BDNF) gene is a plausible candidate for early-emerging negative emotionality (NE), and evidence suggests that the effects of this gene may be especially salient in the context of familial risk for child maladjustment. We therefore examined whether the BDNF val66met polymorphism was associated with child NE in the context of parental depression and relationship discord. A sample of 413 three-year-old children was assessed for NE using standardized laboratory measures. Parents completed clinical interviews and a measure of marital satisfaction. Children with at least one BDNF met allele exhibited elevated NE when a parent had a history of depressive disorder, or when relationship discord was present. In contrast, this allele was associated with especially low NE when parent depression was absent, and when the parental relationship was not discordant. Findings suggest that the BDNF met allele confers increased child sensitivity to both positive and negative familial influences. PMID:20921572

Development of a cost-efficient novel method for rapid, concurrent genotyping of five common single nucleotide polymorphisms of the brain derived neurotrophic factor (BDNF) gene by tetra-primer amplification refractory mutation system.

PubMed

Wang, Cathy K; Xu, Michael S; Ross, Colin J; Lo, Ryan; Procyshyn, Ric M; Vila-Rodriguez, Fidel; White, Randall F; Honer, William G; Barr, Alasdair M

2015-09-01

Brain derived neurotrophic factor (BDNF) is a molecular trophic factor that plays a key role in neuronal survival and plasticity. Single nucleotide polymorphisms (SNPs) of the BDNF gene have been associated with specific phenotypic traits in a large number of neuropsychiatric disorders and the response to psychotherapeutic medications in patient populations. Nevertheless, due to study differences and occasionally contrasting findings, substantial further research is required to understand in better detail the association between specific BDNF SNPs and these psychiatric disorders. While considerable progress has been made recently in developing advanced genotyping platforms of SNPs, many high-throughput probe- or array-based detection methods currently available are limited by high costs, slow processing times or access to advanced instrumentation. The polymerase chain reaction (PCR)-based, tetra-primer amplification refractory mutation system (T-ARMS) method is a potential alternative technique for detecting SNP genotypes efficiently, quickly, easily, and cheaply. As a tool in psychopathology research, T-ARMS was shown to be capable of detecting five common SNPs in the BDNF gene (rs6265, rs988748, rs11030104, 11757G/C and rs7103411), which are all SNPs with previously demonstrated clinical relevance to schizophrenia and depression. The present technique therefore represents a suitable protocol for many research laboratories to study the genetic correlates of BDNF in psychiatric disorders. Copyright Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

ACTIVITY-DEPENDENT, STRESS-RESPONSIVE BDNF SIGNALING AND THE QUEST FOR OPTIMAL BRAIN HEALTH AND RESILIENCE THROUGHOUT THE LIFESPAN

PubMed Central

Rothman, S. M.; Mattson, M. P.

2013-01-01

During development of the nervous system, the formation of connections (synapses) between neurons is dependent upon electrical activity in those neurons, and neurotrophic factors produced by target cells play a pivotal role in such activity-dependent sculpting of the neural networks. A similar interplay between neurotransmitter and neurotrophic factor signaling pathways mediates adaptive responses of neural networks to environmental demands in adult mammals, with the excitatory neurotransmitter glutamate and brain-derived neurotrophic factor (BDNF) being particularly prominent regulators of synaptic plasticity throughout the central nervous system. Optimal brain health throughout the lifespan is promoted by intermittent challenges such as exercise, cognitive stimulation and dietary energy restriction, that subject neurons to activity-related metabolic stress. At the molecular level, such challenges to neurons result in the production of proteins involved in neurogenesis, learning and memory and neuronal survival; examples include proteins that regulate mitochondrial biogenesis, protein quality control, and resistance of cells to oxidative, metabolic and proteotoxic stress. BDNF signaling mediates up-regulation of several such proteins including the protein chaperone GRP-78, antioxidant enzymes, the cell survival protein Bcl-2, and the DNA repair enzyme APE1. Insufficient exposure to such challenges, genetic factors may conspire to impair BDNF production and/or signaling resulting in the vulnerability of the brain to injury and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s diseases. Further, BDNF signaling is negatively regulated by glucocorticoids. Glucocorticoids impair synaptic plasticity in the brain by negatively regulating spine density, neurogenesis and long-term potentiation, effects that are potentially linked to glucocorticoid regulation of BDNF. Findings suggest that BDNF signaling in specific brain regions mediates

Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF).

PubMed

Genzer, Yoni; Dadon, Maayan; Burg, Chen; Chapnik, Nava; Froy, Oren

2016-07-15

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain and its decreased levels are associated with the development of obesity and neurodegeneration. Our aim was to test the effect of dietary fat, its timing and the circadian clock on the expression of BDNF and associated signaling pathways in mouse brain and liver. Bdnf mRNA oscillated robustly in brain and liver, but with a 12-h shift between the tissues. Brain and liver Bdnf mRNA showed a 12-h phase shift when fed ketogenic diet (KD) compared with high-fat diet (HFD) or low-fat diet (LFD). Brain or liver Bdnf mRNA did not show the typical phase advance usually seen under time-restricted feeding (RF). Clock knockdown in HT-4 hippocampal neurons led to 86% up-regulation of Bdnf mRNA, whereas it led to 60% down-regulation in AML-12 hepatocytes. Dietary fat in mice or cultured hepatocytes and hippocampal neurons led to increased Bdnf mRNA expression. At the protein level, HFD increased the ratio of the mature BDNF protein (mBDNF) to its precursor (proBDNF). In the liver, RF under LFD or HFD reduced the mBDNF/proBDNF ratio. In the brain, the two signaling pathways related to BDNF, mTOR and AMPK, showed reduced and increased levels, respectively, under timed HFD. In the liver, the reverse was achieved. In summary, Bdnf expression is mediated by the circadian clock and dietary fat. Although RF does not affect its expression phase, in the brain, when combined with high-fat diet, it leads to a unique metabolic state in which AMPK is activated, mTOR is down-regulated and the levels of mBDNF are high. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A significant association between BDNF promoter methylation and the risk of drug addiction.

PubMed

Xu, Xuting; Ji, Huihui; Liu, Guili; Wang, Qinwen; Liu, Huifen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Zhou, Wenhua; Duan, Shiwei

2016-06-10

As a member of the neurotrophic factor family, brain derived neurotrophic factor (BDNF) plays an important role in the survival and differentiation of neurons. The aim of our work was to evaluate the role of BDNF promoter methylation in drug addiction. A total of 60 drug abusers (30 heroin and 30 methylamphetamine addicts) and 52 healthy age- and gender-matched controls were recruited for the current case control study. Bisulfite pyrosequencing technology was used to determine the methylation levels of five CpGs (CpG1-5) on the BDNF promoter. Among the five CpGs, CpG5 methylation was significantly lower in drug abusers than controls. Moreover, significant associations were found between CpG5 methylation and addictive phenotypes including tension-anxiety, anger-hostility, fatigue-inertia, and depression-dejection. In addition, luciferase assay showed that the DNA fragment of BDNF promoter played a key role in the regulation of gene expression. Our results suggest that BDNF promoter methylation is associated with drug addiction, although further studies are needed to understand the mechanisms by which BDNF promoter methylation contributes to the pathophysiology of drug addiction. Copyright © 2016. Published by Elsevier B.V.

Conformations of the Huntingtin N-term in aqueous solution from atomistic simulations.

PubMed

Rossetti, Giulia; Cossio, Pilar; Laio, Alessandro; Carloni, Paolo

2011-10-03

The first 17 amino acids of Huntingtin protein (N17) play a crucial role in the protein's aggregation. Here we predict its free energy landscape in aqueous solution by using bias exchange metadynamics. All our findings are consistent with experimental data. N17 populates four main kinetic basins, which interconvert on the microsecond time-scale. The most populated basin (about 75%) is a random coil, with an extended flat exposed hydrophobic surface. This might create a hydrophobic seed promoting Huntingtin aggregation. The other main populated basins contain helical conformations, which could facilitate N17 binding on its cellular targets. Copyright © 2011. Published by Elsevier B.V.

Targeted retrograde transfection of adenovirus vector carrying brain-derived neurotrophic factor gene prevents loss of mouse (twy/twy) anterior horn neurons in vivo sustaining mechanical compression.

PubMed

Xu, Kan; Uchida, Kenzo; Nakajima, Hideaki; Kobayashi, Shigeru; Baba, Hisatoshi

2006-08-01

Immunohistochemical analysis after adenovirus (AdV)-mediated BDNF gene transfer in and around the area of mechanical compression in the cervical spinal cord of the hyperostotic mouse (twy/twy). To investigate the neuroprotective effect of targeted AdV-BDNF gene transfection in the twy mouse with spontaneous chronic compression of the spinal cord motoneurons. Several studies reported the neuroprotective effects of neurotrophins on injured spinal cord. However, no report has described the effect of targeted retrograde neurotrophic gene delivery on motoneuron survival in chronic compression lesions of the cervical spinal cord resembling lesions of myelopathy. LacZ marker gene using adenoviral vector (AdV-LacZ) was used to evaluate retrograde delivery from the sternomastoid muscle in adult twy mice (16-week-old) and (control). Four weeks after the AdV-LacZ or AdV-BDNF injection, the compressed cervical spinal cord was removed en bloc for immunohistologic investigation of b-galactosidase activity and immunoreactivity and immunoblot analyses of BDNF. The number of anterior horn neurons was counted using Nissl, ChAT and AChE staining. Spinal accessory motoneurons between C1 and C3 segments were successfully transfected by AdV-LacZ in both twy and ICR mice after targeted intramuscular injection. Immunoreactivity to BDNF was significantly stronger in AdV-BDNF-gene transfected twy mice than in AdV-LacZ-gene transfected mice. At the cord level showing the maximum compression in AdV-BDNF-transfected twy mice, the number of anterior horn neurons was sinificantly higher in the topographic neuronal cell counting of Nissl-, ChAT-, and AChE-stained samples than in AdV-LacZ-injected twy mice. Targeted AdV-BDNF-gene delivery significantly increased Nissl-stained anterior horn neurons and enhanced cholinergic enzyme activities in the twy. Our results suggest that targeted retrograde AdV-BDNF-gene in vivo delivery may enhance neuronal survival even under chronic mechanical compression.

Increased production of BDNF in colonic epithelial cells induced by fecal supernatants from diarrheic IBS patients.

PubMed

Wang, Peng; Chen, Fei-Xue; Du, Chao; Li, Chang-Qing; Yu, Yan-Bo; Zuo, Xiu-Li; Li, Yan-Qing

2015-05-22

Colonic brain-derived neurotrophic factor (BDNF) plays an essential role in pathogenesis of abdominal pain in diarrhea-predominant irritable bowel syndrome (IBS-D), but regulation on its expression remains unclear. We investigated the role of fecal supernatants (FSN) from IBS-D patients on regulating BDNF expression in colonic epithelial cells of human and mice. Using human Caco-2 cells, we found that IBS-D FSN significantly increased BDNF mRNA and protein levels compared to control FSN, which were remarkably suppressed by the serine protease inhibitor. To further explore the potential mechanisms, we investigated the impact of protease-activated receptor-2 (PAR-2) on BDNF expression. We found a significant increase in PAR-2 expression in Caco-2 after IBS-D FSN stimulation. Knockdown of PAR-2 significantly inhibited IBS-D FSN-induced upregulation of BDNF. Moreover, we found that phosphorylation of p38 MAPK, not NF-κB p65, contributed to PAR-2-mediated BDNF overexpression. To confirm these results, we intracolonically infused IBS-D or control FSN in mice and found that IBS-D FSN significantly elevated colonic BDNF and visceral hypersensitivity in mice, which were both suppressed by the inhibitor of serine protease or antagonist of PAR-2. Together, our data indicate that activation of PAR-2 signaling by IBS-D FSN promotes expression of colonic BDNF, thereby contributing to IBS-like visceral hypersensitivity.

BDNF Expression in Perirhinal Cortex is Associated with Exercise-Induced Improvement in Object Recognition Memory

PubMed Central

Hopkins, Michael E.; Bucci, David J.

2010-01-01

Physical exercise induces widespread neurobiological adaptations and improves learning and memory. Most research in this field has focused on hippocampus-based spatial tasks and changes in brain-derived neurotrophic factor (BDNF) as a putative substrate underlying exercise-induced cognitive improvements. Chronic exercise can also be anxiolytic and causes adaptive changes in stress reactivity. The present study employed a perirhinal cortex-dependent object recognition task as well as the elevated plus maze to directly test for interactions between the cognitive and anxiolytic effects of exercise in male Long Evans rats. Hippocampal and perirhinal cortex tissue was collected to determine whether the relationship between BDNF and cognitive performance extends to this non-spatial and non-hippocampal-dependent task. We also examined whether the cognitive improvements persisted once the exercise regimen was terminated. Our data indicate that 4 weeks of voluntary exercise every-other-day improved object recognition memory. Importantly, BDNF expression in the perirhinal cortex of exercising rats was strongly correlated with object recognition memory. Exercise also decreased anxiety-like behavior, however there was no evidence to support a relationship between anxiety-like behavior and performance on the novel object recognition task. There was a trend for a negative relationship between anxiety-like behavior and hippocampal BDNF. Neither the cognitive improvements nor the relationship between cognitive function and perirhinal BDNF levels persisted after 2 weeks of inactivity. These are the first data demonstrating that region-specific changes in BDNF protein levels are correlated with exercise-induced improvements in non-spatial memory, mediated by structures outside the hippocampus and are consistent with the theory that, with regard to object recognition, the anxiolytic and cognitive effects of exercise may be mediated through separable mechanisms. PMID:20601027

Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

PubMed Central

2013-01-01

Background Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. Methods Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. Results LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. Conclusions We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF. PMID:23363775

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

PubMed Central

Lee, Bridgin G.; Anastasia, Agustin; Hempstead, Barbara L.; Lee, Francis S.

2015-01-01

Introduction: Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. Methods: This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNFMet/Met) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Results: Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNFMet/Met mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNFMet/Met mice; and (3) an increase in BDNF prodomain in BDNFMet/Met mice following nicotine withdrawal. Conclusions: Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNFMet/Met mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. PMID:25744957

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors.

PubMed

Mills, Ian G; Gaughan, Luke; Robson, Craig; Ross, Theodora; McCracken, Stuart; Kelly, John; Neal, David E

2005-07-18

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription.

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors

PubMed Central

Mills, Ian G.; Gaughan, Luke; Robson, Craig; Ross, Theodora; McCracken, Stuart; Kelly, John; Neal, David E.

2005-01-01

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription. PMID:16027218

BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

PubMed Central

Terracciano, Antonio; Tanaka, Toshiko; Sutin, Angelina R; Deiana, Barbara; Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Maschio, Andrea; Uda, Manuela; Ferrucci, Luigi; Schlessinger, David; Costa, Paul T

2010-01-01

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism. PMID:20042999

Functions of Huntingtin in Germ Layer Specification and Organogenesis

PubMed Central

Nguyen, Giang D.; Molero, Aldrin E.; Gokhan, Solen; Mehler, Mark F.

2013-01-01

Huntington’s disease (HD) is a neurodegenerative disease caused by abnormal polyglutamine expansion in the huntingtin protein (Htt). Although both Htt and the HD pathogenic mutation (mHtt) are implicated in early developmental events, their individual involvement has not been adequately explored. In order to better define the developmental functions and pathological consequences of the normal and mutant proteins, respectively, we employed embryonic stem cell (ESC) expansion, differentiation and induction experiments using huntingtin knock-out (KO) and mutant huntingtin knock-in (Q111) mouse ESC lines. In KO ESCs, we observed impairments in the spontaneous specification and survival of ectodermal and mesodermal lineages during embryoid body formation and under inductive conditions using retinoic acid and Wnt3A, respectively. Ablation of BAX improves cell survival, but failed to correct defects in germ layer specification. In addition, we observed ensuing impairments in the specification and maturation of neural, hepatic, pancreatic and cardiomyocyte lineages. These developmental deficits occurred in concert with alterations in Notch, Hes1 and STAT3 signaling pathways. Moreover, in Q111 ESCs, we observed differential developmental stage-specific alterations in lineage specification and maturation. We also observed changes in Notch/STAT3 expression and activation. Our observations underscore essential roles of Htt in the specification of ectoderm, endoderm and mesoderm, in the specification of neural and non-neural organ-specific lineages, as well as cell survival during early embryogenesis. Remarkably, these developmental events are differentially deregulated by mHtt, raising the possibility that HD-associated early developmental impairments may contribute not only to region-specific neurodegeneration, but also to non-neural co-morbidities. PMID:23967334

BDNF-Val66Met-Polymorphism Impact on Cortical Plasticity in Schizophrenia Patients: A Proof-of-Concept Study

PubMed Central

Nitsche, Michael A.; Wobrock, Thomas; Bunse, Tilmann; Rein, Bettina; Herrmann, Maximiliane; Schmitt, Andrea; Nieratschker, Vanessa; Witt, Stephanie H.; Rietschel, Marcella; Falkai, Peter; Hasan, Alkomiet

2015-01-01

Background: Brain-derived neurotrophic factor (BDNF) has been shown to be a moderator of neuroplasticity. A frequent BDNF-polymorphism (Val66Met) is associated with impairments of cortical plasticity. In patients with schizophrenia, reduced neuroplastic responses following non-invasive brain stimulation have been reported consistently. Various studies have indicated a relationship between the BDNF-Val66Met-polymorphism and motor-cortical plasticity in healthy individuals, but schizophrenia patients have yet to be investigated. The aim of this proof-of-concept study was, therefore, to test the impact of the BDNF-Val66Met-polymorphism on inhibitory and facilitatory cortical plasticity in schizophrenia patients. Methods: Cortical plasticity was investigated in 22 schizophrenia patients and 35 healthy controls using anodal and cathodal transcranial direct-current stimulation (tDCS) applied to the left primary motor cortex. Animal and human research indicates that excitability shifts following anodal and cathodal tDCS are related to molecular long-term potentiation and long-term depression. To test motor-cortical excitability before and after tDCS, well-established single- and paired-pulse transcranial magnetic stimulation protocols were applied. Results: Our analysis revealed increased glutamate-mediated intracortical facilitation in met-heterozygotes compared to val-homozygotes at baseline. Following cathodal tDCS, schizophrenia met-heterozygotes had reduced gamma-amino-butyric-acid-mediated short-interval intracortical inhibition, whereas healthy met-heterozygotes displayed the opposite effect. The BDNF-Val66Met-polymorphism did not influence single-pulse motor-evoked potential amplitudes after tDCS. Conclusions: These preliminary findings support the notion of an association of the BDNF-Val66Met-polymorphism with observable alterations in plasticity following cathodal tDCS in schizophrenia patients. This indicates a complex interaction between inhibitory

Changes in the striatal proteome of YAC128Q mice exhibit gene-environment interactions between mutant huntingtin and manganese.

PubMed

Wegrzynowicz, Michal; Holt, Hunter K; Friedman, David B; Bowman, Aaron B

2012-02-03

Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a CAG repeat within the Huntingtin (HTT) gene, though the clinical presentation of disease and age-of-onset are strongly influenced by ill-defined environmental factors. We recently reported a gene-environment interaction wherein expression of mutant HTT is associated with neuroprotection against manganese (Mn) toxicity. Here, we are testing the hypothesis that this interaction may be manifested by altered protein expression patterns in striatum, a primary target of both neurodegeneration in HD and neurotoxicity of Mn. To this end, we compared striatal proteomes of wild-type and HD (YAC128Q) mice exposed to vehicle or Mn. Principal component analysis of proteomic data revealed that Mn exposure disrupted a segregation of WT versus mutant proteomes by the major principal component observed in vehicle-exposed mice. Identification of altered proteins revealed novel markers of Mn toxicity, particularly proteins involved in glycolysis, excitotoxicity, and cytoskeletal dynamics. In addition, YAC128Q-dependent changes suggest that axonal pathology may be an early feature in HD pathogenesis. Finally, for several proteins, genotype-specific responses to Mn were observed. These differences include increased sensitivity to exposure in YAC128Q mice (UBQLN1) and amelioration of some mutant HTT-induced alterations (SAE1, ENO1). We conclude that the interaction of Mn and mutant HTT may suppress proteomic phenotypes of YAC128Q mice, which could reveal potential targets in novel treatment strategies for HD.

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin*

PubMed Central

Wu, Shuai; Zheng, Shui-Di; Huang, Hong-Ling; Yan, Li-Chong; Yin, Xiao-Fei; Xu, Hai-Neng; Zhang, Kang-Jian; Gui, Jing-Hua; Chu, Liang; Liu, Xin-Yuan

2013-01-01

Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration. PMID:24165128

Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)*

PubMed Central

Datta, Moumita; Bhattacharyya, Nitai P.

2011-01-01

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease. PMID:21832040

Regulation of RE1 protein silencing transcription factor (REST) expression by HIP1 protein interactor (HIPPI).

PubMed

Datta, Moumita; Bhattacharyya, Nitai P

2011-09-30

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease.

Adeno-Associated Viral Vector Serotype DJ-Mediated Overexpression of N171-82Q-Mutant Huntingtin in the Striatum of Juvenile Mice Is a New Model for Huntington's Disease.

PubMed

Jang, Minhee; Lee, Seung Eun; Cho, Ik-Hyun

2018-01-01

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. HD is caused by an expansion of CAG repeats in the huntingtin ( HTT ) gene in various areas of the brain including striatum. There are few suitable animal models to study the pathogenesis of HD and validate therapeutic strategies. Recombinant adeno-associated viral (AAV) vectors successfully transfer foreign genes to the brain of adult mammalians. In this article, we report a novel mouse model of HD generated by bilateral intrastriatal injection of AAV vector serotype DJ (AAV-DJ) containing N171-82Q mutant HTT (82Q) and N171-18Q wild type HTT (18Q; sham). The AAV-DJ-82Q model displayed motor dysfunctions in pole and rotarod tests beginning 4 weeks after viral infection in juvenile mice (8 weeks after birth). They showed behaviors reflecting neurodegeneration. They also showed increased apoptosis, robust glial activation and upregulated representative inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), mediators (cyclooxygenase-2 and inducible nitric oxide synthase) and signaling pathways (nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3)) in the striatum at 10 weeks after viral infection (14 weeks after birth) via successful transfection of mutant HTT into neurons, microglia, and astrocytes in the striatum. However, little evidence of any of these events was found in mice infected with the AAV-DJ-18Q expressing construct. Intrastriatal injection of AAV-DJ-82Q might be useful as a novel in vivo model to investigate the biology of truncated N-terminal fragment (N171) in the striatum and to explore the efficacy of therapeutic strategies for HD.

Early Life Stress Effects on Glucocorticoid—BDNF Interplay in the Hippocampus

PubMed Central

Daskalakis, Nikolaos P.; De Kloet, Edo Ronald; Yehuda, Rachel; Malaspina, Dolores; Kranz, Thorsten M.

2015-01-01

Early life stress (ELS) is implicated in the etiology of multiple psychiatric disorders. Important biological effects of ELS are manifested in stress-susceptible regions of the hippocampus and are partially mediated by long-term effects on glucocorticoid (GC) and/or neurotrophin signaling pathways. GC-signaling mediates the regulation of stress response to maintain homeostasis, while neurotrophin signaling plays a key role in neuronal outgrowth and is crucial for axonal guidance and synaptic integrity. The neurotrophin and GC-signaling pathways co-exist throughout the central nervous system (CNS), particularly in the hippocampus, which has high expression levels of glucocorticoid-receptors (GR) and mineralocorticoid-receptors (MR) as well as brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB). This review addresses the effects of ELS paradigms on GC- and BDNF-dependent mechanisms and their crosstalk in the hippocampus, including potential implications for the pathogenesis of common stress-related disorders. PMID:26635521

Epigenetic Modification of Hippocampal Bdnf DNA in Adult Rats in an Animal Model of Post-Traumatic Stress Disorder

PubMed Central

Roth, Tania L.; Zoladz, Phillip R.; Sweatt, J. David; Diamond, David M.

2011-01-01

Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and BdnfDNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed BdnfDNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased BdnfDNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in BdnfDNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of BdnfmRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnfgene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal BdnfDNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD. PMID:21306736

Complete spinal cord injury (SCI) transforms how brain derived neurotrophic factor (BDNF) affects nociceptive sensitization.

PubMed

Huang, Yung-Jen; Lee, Kuan H; Grau, James W

2017-02-01

Noxious stimulation can induce a lasting increase in neural excitability within the spinal cord (central sensitization) that can promote pain and disrupt adaptive function (maladaptive plasticity). Brain-derived neurotrophic factor (BDNF) is known to regulate the development of plasticity and has been shown to impact the development of spinally-mediated central sensitization. The latter effect has been linked to an alteration in GABA-dependent inhibition. Prior studies have shown that, in spinally transected rats, exposure to regular (fixed spaced) stimulation can counter the development of maladaptive plasticity and have linked this effect to an up-regulation of BDNF. Here it is shown that application of the irritant capsaicin to one hind paw induces enhanced mechanical reactivity (EMR) after spinal cord injury (SCI) and that the induction of this effect is blocked by pretreatment with fixed spaced shock. This protective effect was eliminated if rats were pretreated with the BDNF sequestering antibody TrkB-IgG. Intrathecal (i.t.) application of BDNF prevented, but did not reverse, capsaicin-induced EMR. BDNF also attenuated cellular indices (ERK and pERK expression) of central sensitization after SCI. In uninjured rats, i.t. BDNF enhanced, rather than attenuated, capsaicin-induced EMR and ERK/pERK expression. These opposing effects were related to a transformation in GABA function. In uninjured rats, BDNF reduced membrane-bound KCC2 and the inhibitory effect of the GABA A agonist muscimol. After SCI, BDNF increased KCC2 expression, which would help restore GABAergic inhibition. The results suggest that SCI transforms how BDNF affects GABA function and imply that the clinical usefulness of BDNF will depend upon the extent of fiber sparing. Copyright © 2016 Elsevier Inc. All rights reserved.

Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement

PubMed Central

Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F.; Escobar, Martha L.

2011-01-01

It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 μg/2 μl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes. PMID:21960964

Ratio of mBDNF to proBDNF for Differential Diagnosis of Major Depressive Disorder and Bipolar Depression.

PubMed

Zhao, Guoqing; Zhang, Chen; Chen, Jun; Su, Yousong; Zhou, Rubai; Wang, Fan; Xia, Weiping; Huang, Jia; Wang, Zuowei; Hu, Yingyan; Cao, Lan; Guo, Xiaoyun; Yuan, Chengmei; Wang, Yong; Yi, Zhenghui; Lu, Weihong; Wu, Yan; Wu, Zhiguo; Hong, Wu; Peng, Daihui; Fang, Yiru

2017-09-01

There is a high rate of misdiagnosis between major depressive disorder (MDD) and bipolar disorder (BD) in clinical practice. Our previous work provided suggestive evidence for brain-derived neurotrophic factor (BDNF) in differentiating BD from MDD. In this study, we aimed to investigate the role of mature BDNF (mBDNF) and its precursor (proBDNF) in distinguishing bipolar depression (BP) from MDD during acute depressive episode. A total of 105 participants, including 44 healthy controls, 37 MDD patients and 24 BP patients, were recruited. Enzyme-linked immunosorbent assay kits were applied to measure plasma mBDNF levels and proBDNF levels of all participants. Plasma mBDNF levels were significantly decreased in BP group than those in MDD group (P = 0.001) and healthy controls (P = 0.002). Significantly higher ratio of mBDNF to proBDNF (M/P) at baseline was showed in MDD group than those in BP group as well as in healthy controls (P = 0.000 and P = 0.000, respectively). The optimal model for discriminating BP was the M/P ratio (area under the ROC curve = 0.858, 95 % CI 0.753-0.963). Furthermore, the M/P ratio was restored to normal levels after antidepressants treatment in MDD group. In summary, our data demonstrated that both plasma mBDNF levels and M/P ratio were lower in BP compared with MDD. These findings further support M/P ratio as a potential differential diagnostic biomarker for BP among patients in depressive episodes.

DNA methylation and single nucleotide variants in the brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) genes are associated with anxiety/depression in older women.

PubMed

Chagnon, Yvon C; Potvin, Olivier; Hudon, Carol; Préville, Michel

2015-01-01

Environmental effects and personal experiences could be expressed in individuals through epigenetic non-structural changes such as DNA methylation. This methylation could up- regulate or down-regulate corresponding gene expressions and modify related phenotypes. DNA methylation increases with aging and could be related to the late expression of some forms of mental disease. The objective of this study was to evaluate the association between anxiety disorders and/or depression in older women and DNA methylation for four genes related to anxiety or depression. Women aged 65 and older with (n = 19) or without (n = 24) anxiety disorders and/or major depressive episode (DSM-IV), were recruited. DNA methylation and single nucleotide variant (SNV) were evaluated from saliva, respectively by pyrosequencing and by PCR, for the following genes: brain-derived neurotrophic factor (BDNF; rs6265), oxytocin receptor (OXTR; rs53576), serotonin transporter (SLC6A4; rs25531), and apolipoprotein E (APOE; rs429358 and rs7412). A greater BDNF DNA methylation was observed in subjects with anxiety/depression compared to control group subjects (Mean: 2.92 SD ± 0.74 vs. 2.34 ± 0.42; p= 0.0026). This difference was more pronounced in subjects carrying the BDNF rs6265 CT genotype (2.99 ± 0.41 vs. 2.27 ± 0.26; p= 0.0006) than those carrying the CC genotype (p= 0.0332); no subjects with the TT genotype were observed. For OXTR, a greater DNA methylation was observed in subjects with anxiety/depression, but only for those carrying the AA genotype of the OXTR rs53576 SNV, more particularly at one out of the seven CpGs studied (7.01 ± 0.94 vs. 4.44 ± 1.11; p= 0.0063). No significant differences were observed for APOE and SLC6A4. These results suggest that DNA methylation in interaction with SNV variations in BDNF and OXTR, are associated with the occurrence of anxiety/depression in older women.

VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism.

PubMed

Lin, Wei-Jye; Jiang, Cheng; Sadahiro, Masato; Bozdagi, Ozlem; Vulchanova, Lucy; Alberini, Cristina M; Salton, Stephen R

2015-07-15

Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition. Identification of additional modulators of cognitive behavior that regulate activity-dependent BDNF secretion and/or potentiate TrkB receptor signaling would therefore be of considerable interest. In this study, we show in the adult mouse hippocampus that expression of the granin family gene Vgf and secretion of its C-terminal VGF-derived peptide TLQP-62 are required for fear memory formation. We found that hippocampal VGF expression and TLQP-62 levels were transiently induced after fear memory training and that sequestering secreted TLQP-62 peptide in the hippocampus immediately after training impaired memory formation. Reduced VGF expression was found to impair learning-evoked Rac1 induction and phosphorylation of the synaptic plasticity markers cofilin and synapsin in the adult mouse hippocampus. Moreover, TLQP-62 induced acute, transient activation of the TrkB receptor and subsequent CREB phosphorylation in hippocampal slice preparations and its administration immediately after training enhanced long-term memory formation. A critical role of BDNF-TrkB signaling as a downstream effector in VGF/TLQP-62-mediated memory consolidation was further revealed by posttraining activation of BDNF-TrkB signaling, which rescued impaired fear memory resulting from hippocampal administration of anti-VGF antibodies or germline VGF ablation in mice. We propose that VGF is a critical component of a positive BDNF-TrkB regulatory loop and, upon its induced expression by memory training, the TLQP-62 peptide rapidly reinforces BDNF-TrkB signaling, regulating hippocampal memory consolidation. Identification of the cellular and molecular mechanisms that regulate long-term memory formation and storage may provide alternative treatment modalities for degenerative and neuropsychiatric memory disorders. The neurotrophin BDNF plays a prominent role in cognitive

VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism

PubMed Central

Lin, Wei-Jye; Jiang, Cheng; Sadahiro, Masato; Bozdagi, Ozlem; Vulchanova, Lucy; Alberini, Cristina M.

2015-01-01

Regulated expression and secretion of BDNF, which activates TrkB receptor signaling, is known to play a critical role in cognition. Identification of additional modulators of cognitive behavior that regulate activity-dependent BDNF secretion and/or potentiate TrkB receptor signaling would therefore be of considerable interest. In this study, we show in the adult mouse hippocampus that expression of the granin family gene Vgf and secretion of its C-terminal VGF-derived peptide TLQP-62 are required for fear memory formation. We found that hippocampal VGF expression and TLQP-62 levels were transiently induced after fear memory training and that sequestering secreted TLQP-62 peptide in the hippocampus immediately after training impaired memory formation. Reduced VGF expression was found to impair learning-evoked Rac1 induction and phosphorylation of the synaptic plasticity markers cofilin and synapsin in the adult mouse hippocampus. Moreover, TLQP-62 induced acute, transient activation of the TrkB receptor and subsequent CREB phosphorylation in hippocampal slice preparations and its administration immediately after training enhanced long-term memory formation. A critical role of BDNF-TrkB signaling as a downstream effector in VGF/TLQP-62-mediated memory consolidation was further revealed by posttraining activation of BDNF-TrkB signaling, which rescued impaired fear memory resulting from hippocampal administration of anti-VGF antibodies or germline VGF ablation in mice. We propose that VGF is a critical component of a positive BDNF-TrkB regulatory loop and, upon its induced expression by memory training, the TLQP-62 peptide rapidly reinforces BDNF-TrkB signaling, regulating hippocampal memory consolidation. SIGNIFICANCE STATEMENT Identification of the cellular and molecular mechanisms that regulate long-term memory formation and storage may provide alternative treatment modalities for degenerative and neuropsychiatric memory disorders. The neurotrophin BDNF plays a

The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes.

PubMed

Beste, Christian; Schneider, Daniel; Epplen, Jörg T; Arning, Larissa

2011-01-01

The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes. Copyright © 2010 Elsevier Ltd. All rights reserved.

A Critical Role of Mitochondria in BDNF-Associated Synaptic Plasticity After One-Week Vortioxetine Treatment.

PubMed

Chen, Fenghua; Danladi, Jibrin; Ardalan, Maryam; Elfving, Betina; Müller, Heidi K; Wegener, Gregers; Sanchez, Connie; Nyengaard, Jens R

2018-06-01

Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling. Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine's modulation of serotonin receptors.

Serum proBDNF/BDNF and response to fluvoxamine in drug-naïve first-episode major depressive disorder patients.

PubMed

Yoshimura, Reiji; Kishi, Taro; Hori, Hikaru; Atake, Kiyokazu; Katsuki, Asuka; Nakano-Umene, Wakako; Ikenouchi-Sugita, Atsuko; Iwata, Nakao; Nakamura, Jun

2014-01-01

We investigated the association between serum proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and response to fluvoxamine in patients with major depressive disorder (MDD) using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR): physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Fifty-one patients with MDD (M/F, 19:32; age, 38 ± 19 years) and 51 healthy controls (M/F, 22:29; age, 34 ± 17 years) were studied using DSM-IV-TR: physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Serum levels of proBDNF and MDNF were measured by sandwich enzyme-linked immunosorbent assay (ELISA). Serum mature BDNF levels in the MDD patients were significantly lower than those in the healthy controls (t = 3.046, p = 0.0018). On the other hand, no difference was found in serum proBDNF between the MDD patients and the healthy controls (t = -0.979, p = 0.833). A trend of negative correlation was found between baseline serum BDNF and baseline scores of the 17 items of the Hamilton Rating Scale for Depression (HAMD17) (r = -0.183, p = 0.071). No correlation was however found between HAMD17 scores and proBDNF at baseline (r = 0.092, p = 0.421). Furthermore, no correlation was observed between baseline HAMD17 scores and baseline proBDNF/BDNF (r = -0.130, p = 0.190). No changes were observed in serum levels of proBDNF and BDNF during the treatment periods. These results suggest that there is no association between serum proBDNF/BDNF and fluvoxamine response in MDD patients at least within 4 weeks of the treatment.

Adeno-Associated Viral Vector Serotype DJ-Mediated Overexpression of N171-82Q-Mutant Huntingtin in the Striatum of Juvenile Mice Is a New Model for Huntington’s Disease

PubMed Central

Jang, Minhee; Lee, Seung Eun; Cho, Ik-Hyun

2018-01-01

Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. HD is caused by an expansion of CAG repeats in the huntingtin (HTT) gene in various areas of the brain including striatum. There are few suitable animal models to study the pathogenesis of HD and validate therapeutic strategies. Recombinant adeno-associated viral (AAV) vectors successfully transfer foreign genes to the brain of adult mammalians. In this article, we report a novel mouse model of HD generated by bilateral intrastriatal injection of AAV vector serotype DJ (AAV-DJ) containing N171-82Q mutant HTT (82Q) and N171-18Q wild type HTT (18Q; sham). The AAV-DJ-82Q model displayed motor dysfunctions in pole and rotarod tests beginning 4 weeks after viral infection in juvenile mice (8 weeks after birth). They showed behaviors reflecting neurodegeneration. They also showed increased apoptosis, robust glial activation and upregulated representative inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), mediators (cyclooxygenase-2 and inducible nitric oxide synthase) and signaling pathways (nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3)) in the striatum at 10 weeks after viral infection (14 weeks after birth) via successful transfection of mutant HTT into neurons, microglia, and astrocytes in the striatum. However, little evidence of any of these events was found in mice infected with the AAV-DJ-18Q expressing construct. Intrastriatal injection of AAV-DJ-82Q might be useful as a novel in vivo model to investigate the biology of truncated N-terminal fragment (N171) in the striatum and to explore the efficacy of therapeutic strategies for HD. PMID:29946240

Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/- BDNF mutant mice.

PubMed

Dluzen, D E; Gao, X; Story, G M; Anderson, L I; Kucera, J; Walro, J M

2001-07-01

Deletion of a single copy of the BDNF gene has been shown to affect the nigrostriatal dopaminergic system of young adult BDNF mice. In the present report we evaluated various indices of nigrostriatal dopaminergic function between 9-month-old wild-type (+/+) and heterozygous (+/-) BDNF mutant mice. Performance in a sensorimotor beam walking task was significantly decreased in +/- mice as indicated by increased times required to traverse both a wide (21 mm) and narrow (6 mm) beam. No differences in spontaneous locomotor behavior were observed between the +/+ and +/- mice. Amphetamine-stimulated (5 mg/kg) locomotor behavior was increased to a greater degree in the +/- mice, with the number of movements performed by these mice being significantly greater than their +/+ controls. Corpus striatal dopamine concentrations were significantly greater in the +/- BDNF mice. The absence of any significant differences for dopamine concentrations within the hypothalamus and olfactory bulb of these mice, as well as an absence of any difference in striatal norepinephrine concentrations, suggested a relative specificity of these effects to the corpus striatum. Both the +/- and +/+ mice showed similar reductions in striatal dopamine concentrations in response to a neurotoxic regimen of methamphetamine (20 mg/kg). Collectively these data show increased levels of striatal dopamine concentrations associated with altered behavioral responses involving the nigrostriatal dopaminergic system within the heterozygous BDNF mutant mice. Copyright 2001 Academic Press.

Maternal inheritance of BDNF deletion, with phenotype of obesity and developmental delay in mother and child.

PubMed

Harcourt, Brooke E; Bullen, Denise V R; Kao, Kung-Ting; Tassoni, Daniella; Alexander, Erin J; Burgess, Trent; White, Susan M; Sabin, Matthew A

2018-01-01

Childhood obesity is a significant world health problem. Understanding the genetic and environmental factors contributing to the development of obesity in childhood is important for the rational design of strategies for obesity prevention and treatment. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth and development of the central nervous system, there is also an evidence that BDNF plays a role in regulation of appetite. Disruption of the expression of this gene in a child has been previously reported to result in a phenotype of severe obesity, hyperphagia, impaired cognitive function, and hyperactivity. We report a mother and child, both with micro-deletions encompassing the BDNF gene locus, who both have obesity and developmental delay, although without hyperactivity. This report highlights the maternal inheritance of a rare genetic cause of childhood obesity. © 2017 Wiley Periodicals, Inc.

RS 10767664 gene variant in Brain Derived Neurotrophic Factor (BDNF) affect metabolic changes and insulin resistance after a standard hypocaloric diet.

PubMed

de Luis, Daniel Antonio; Fernández Ovalle, H; Izaola, O; Primo, D; Aller, Rocío

2018-02-01

Role of BDNF variants on change in body weight and cardiovascular risk factors after weight loss remains unclear in obese patients. Our aim was to analyze the effects of rs10767664 BDNF gene polymorphism on body weight, cardiovascular risk factors and serum adipokine levels after a standard hypocaloric diet in obese subjects. A Caucasian population of 80 obese patients was analyzed before and after 3months on a standard hypocaloric diet. Fifty patients (62.5%) had the genotype AA and 30 (37.5%) subjects had the next genotypes; AT (25 patients, 31.3%) or TT (5 study subjects, 6.3%) (second group). In non T allele carriers, the decreases in weight-3.4±2.9kg (T allele group -1.7±2.0kg:p=0.01), BMI -1.5±0.2kg (T allele group -1.2±0.5kg:p=0.02), fat mass-2.3±1.1kg (T allele group -1.7±0.9kg:p=0.009), waist circumference-3.8±2.4cm (T allele group -2.1±3.1cm:p=0.008), triglycerides -13.2±7.5mg/dl (T allele group +2.8±1.2mg/dl:p=0.02), insulin -2.1±1.9mUI/L (T allele group -0.3±1.0mUI/L:p=0.01), HOMA-IR -0.9±0.4 (T allele group -0.1±0.8:p=0.01) and leptin -10.1±9.5ng/dl (T allele group -3.1±0.2ng/dl:p=0.01) were higher than T allele carriers. rs10767664 variant of BDNF gene modify anthropometric and biochemical changes after weight loss with a hypocaloric diet. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2(308/y) Mouse Model.

PubMed

Rousseaud, Audrey; Delépine, Chloé; Nectoux, Juliette; Billuart, Pierre; Bienvenu, Thierry

2015-08-01

Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in methyl-CpG-binding protein 2 (MECP2), which encodes a transcriptional modulator of many genes including BDNF. BDNF comprises nine distinct promoter regions, each triggering the expression of a specific transcript. The role of this diversity of transcripts remains unknown. MeCP2 being highly expressed in neurons, RTT was initially considered as a neuronal disease. However, recent studies have shown that MeCP2 was also expressed in astrocytes. Though several studies explored Bdnf IV expression in Mecp2-deficient mice, the differential expression of Bdnf isoforms in Mecp2-deficient neurons and astrocytes was never studied. By using TaqMan technology and a mouse model expressing a truncated Mecp2 (Mecp2(308/y)), we firstly showed in neurons that Bdnf transcripts containing exon I, IIb, IIc, IV, and VI are prominently expressed, whereas in astrocytes, Bdnf transcript containing exon VI is preferentially expressed, suggesting a specific regulation of Bdnf expression at the cellular level. Secondly, we confirmed the repressive role of Mecp2 only on the expression of Bdnf VI in neurons. Our data suggested that the truncated Mecp2 protein maintains its function on Bdnf expression regulation in neurons and in astrocytes. Interestingly, we observed that Bdnf transcripts (I and IXA), regulated by neural activity induced by bicuculline in Mecp2(308/y) neurons, were not affected by histone deacetylase inhibition. In contrast, Bdnf transcripts (IIb, IIc, and VI), regulated by histone deacetylation, were not affected by bicuculline treatment in wild-type and Mecp2(308/y) neurons. All these results reflect the complexity of regulation of Bdnf gene.

Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder.

PubMed

Yoshida, Taisuke; Ishikawa, Masatomo; Niitsu, Tomihisa; Nakazato, Michiko; Watanabe, Hiroyuki; Shiraishi, Tetsuya; Shiina, Akihiro; Hashimoto, Tasuku; Kanahara, Nobuhisa; Hasegawa, Tadashi; Enohara, Masayo; Kimura, Atsushi; Iyo, Masaomi; Hashimoto, Kenji

2012-01-01

Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD. Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients. These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.

Dysregulation of gene expression in the striatum of BACHD rats expressing full-length mutant huntingtin and associated abnormalities on molecular and protein levels.

PubMed

Yu-Taeger, Libo; Bonin, Michael; Stricker-Shaver, Janice; Riess, Olaf; Nguyen, Hoa Huu Phuc

2017-05-01

Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene coding for the huntingtin protein (HTT). Mutant HTT (mHTT) has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. Utilizing the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, both of which carry full-length human mHTT but with different expression levels. By defining the threshold of significance at p < 0.01, we found 1608 genes and 871 genes differentially expressed in both TG5 and TG9 rats when compared to the wild type littermates, respectively. We only chose the highly up-/down-regulated genes for further analysis by setting an additional threshold of 1.5 fold change. Comparing gene expression profiles of human HD brains and BACHD rats revealed a high concordance in both functional and IPA (Ingenuity Pathway Analysis) canonical pathways relevant to HD. In addition, we investigated the causes leading to gene expression changes at molecular and protein levels in BACHD rats including the involvement of polyQ-containing transcription factors TATA box-binding protein (TBP), Sp1 and CBP as well as the chromatin structure. We demonstrate that the BACHD rat model recapitulates the gene expression changes of the human disease supporting its role as a preclinical research animal model. We also show for the first time that TFIID complex formation is reduced, while soluble TBP is increased in an HD model. This finding suggests that mHTT is a competitor instead of a recruiter of polyQ-containing transcription factors in the transcription process in HD. Copyright © 2017 Elsevier Ltd. All rights reserved.

BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder.

PubMed

Wang, Yuan; Zhang, Haiyin; Li, Ying; Wang, Zhen; Fan, Qing; Yu, Shunying; Lin, Zhiguang; Xiao, Zeping

2015-11-01

Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Our

BDNF in sleep, insomnia, and sleep deprivation.

PubMed

Schmitt, Karen; Holsboer-Trachsler, Edith; Eckert, Anne

2016-01-01

The protein brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors involved in plasticity of neurons in several brain regions. There are numerous evidence that BDNF expression is decreased by experiencing psychological stress and that, accordingly, a lack of neurotrophic support causes major depression. Furthermore, disruption in sleep homeostatic processes results in higher stress vulnerability and is often associated with stress-related mental disorders. Recently, we reported, for the first time, a relationship between BDNF and insomnia and sleep deprivation (SD). Using a biphasic stress model as explanation approach, we discuss here the hypothesis that chronic stress might induce a deregulation of the hypothalamic-pituitary-adrenal system. In the long-term it leads to sleep disturbance and depression as well as decreased BDNF levels, whereas acute stress like SD can be used as therapeutic intervention in some insomniac or depressed patients as compensatory process to normalize BDNF levels. Indeed, partial SD (PSD) induced a fast increase in BDNF serum levels within hours after PSD which is similar to effects seen after ketamine infusion, another fast-acting antidepressant intervention, while traditional antidepressants are characterized by a major delay until treatment response as well as delayed BDNF level increase. Key messages Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology of stress-related mood disorders. The interplay of stress and sleep impacts on BDNF level. Partial sleep deprivation (PSD) shows a fast action on BDNF level increase.

The AMPA receptor potentiator Org 26576 modulates stress-induced transcription of BDNF isoforms in rat hippocampus.

PubMed

Fumagalli, Fabio; Calabrese, Francesca; Luoni, Alessia; Shahid, Mohammed; Racagni, Giorgio; Riva, Marco A

2012-02-01

Brain derived neurotrophic factor (BDNF) is a key mediator of brain plasticity. The modulation of its expression and function is important for cognition and represents a key strategy to enhance neuronal resilience. Within this context, there exists a close interaction between glutamatergic neurotransmission and BDNF activity towards regulating cellular homeostasis and plasticity. The aim of the current study was to investigate the ability of the AMPA receptor potentiator Org 26576 to modulate BDNF expression in selected brain regions under basal conditions or in response to an acute swim stress. Rats subjected to a single intraperitoneal injection with Org 26576 (10mg/kg) or saline were exposed to a swim stress session (5 min) and sacrificed 15 min after the end of stress. Real-time PCR assay was used to determine changes in BDNF transcription in different brain regions. Total BDNF mRNA levels were significantly increased in the hippocampus of animals exposed to the combination of Org 26576 and stress whereas, in prefrontal and frontal cortices, BDNF mRNA levels were modulated by the acute stress, independently from drug treatment. The analysis of BDNF transcripts in the hippocampus revealed a major contribution of exons I and IV. Our results suggest that AMPA receptor potentiation by Org 26576 exerts a positive modulatory influence on BDNF expression during ongoing neuronal activity. Given that these mechanisms are critical for neuronal plasticity, we hypothesized that such changes may facilitate learning/coping mechanisms associated with a mild stressful experience. Copyright © 2011 Elsevier Ltd. All rights reserved.

Transforming properties of the Huntingtin interacting protein 1/ platelet-derived growth factor beta receptor fusion protein.

PubMed

Ross, T S; Gilliland, D G

1999-08-06

We have previously reported that the Huntingtin interacting protein 1 (HIP1) gene is fused to the platelet-derived growth factor beta receptor (PDGFbetaR) gene in a patient with chronic myelomonocytic leukemia. We now show that HIP1/PDGFbetaR oligomerizes, is constitutively tyrosine-phosphorylated, and transforms the murine hematopoietic cell line, Ba/F3, to interleukin-3-independent growth. A kinase-inactive mutant is neither tyrosine-phosphorylated nor able to transform Ba/F3 cells. Oligomerization and kinase activation required the 55-amino acid carboxyl-terminal TALIN homology region but not the leucine zipper domain. Tyrosine phosphorylation of a 130-kDa protein and STAT5 correlates with transformation in cells expressing HIP1/PDGFbetaR and related mutants. A deletion mutant fusion protein that contains only the TALIN homology region of HIP1 fused to PDGFbetaR is incapable of transforming Ba/F3 cells and does not tyrosine-phosphorylate p130 or STAT5, although it is itself constitutively tyrosine-phosphorylated. We have also analyzed cells expressing Tyr --> Phe mutants of HIP1/PDGFbetaR in the known PDGFbetaR SH2 docking sites and report that none of these sites are necessary for STAT5 activation, p130 phosphorylation, or Ba/F3 transformation. The correlation of factor-independent growth of hematopoietic cells with p130 and STAT5 phosphorylation/activation in both the HIP1/PDGFbetaR Tyr --> Phe and deletion mutational variants suggests that both STAT5 and p130 are important for transformation mediated by HIP1/PDGFbetaR.

Assembly of Huntingtin headpiece into α-helical bundles.

PubMed

Ozgur, Beytullah; Sayar, Mehmet

2017-05-24

Protein aggregation is a hallmark of neurodegenerative disorders. In this group of brain-related disorders, a disease-specific "host" protein or fragment misfolds and adopts a metastatic, aggregate-prone conformation. Often, this misfolded conformation is structurally and thermodynamically different from its native state. Intermolecular contacts, which arise in this non-native state, promote aggregation. In this regard, understanding the molecular principles and mechanisms that lead to the formation of such a non-native state and further promote the formation of the critical nucleus for fiber growth is essential. In this study, the authors analyze the aggregation propensity of Huntingtin headpiece (htt NT ), which is known to facilitate the polyQ aggregation, in relation to the helix mediated aggregation mechanism proposed by the Wetzel group. The authors demonstrate that even though htt NT displays a degenerate conformational spectrum on its own, interfaces of macroscopic or molecular origin can promote the α-helix conformation, eliminating all other alternatives in the conformational phase space. Our findings indicate that htt NT molecules do not have a strong orientational preference for parallel or antiparallel orientation of the helices within the aggregate. However, a parallel packed bundle of helices would support the idea of increased polyglutamine concentration, to pave the way for cross-β structures.

A Critical Role of Mitochondria in BDNF-Associated Synaptic Plasticity After One-Week Vortioxetine Treatment

PubMed Central

Chen, Fenghua; Danladi, Jibrin; Ardalan, Maryam; Elfving, Betina; Müller, Heidi K; Sanchez, Connie; Nyengaard, Jens R

2018-01-01

Abstract Background Preclinical studies have indicated that antidepressant effect of vortioxetine involves increased synaptic plasticity and promotion of spine maturation. Mitochondria dysfunction may contribute to the pathophysiological basis of major depressive disorder. Taking into consideration that vortioxetine increases spine number and dendritic branching in hippocampus CA1 faster than fluoxetine, we hypothesize that new spines induced by vortioxetine can rapidly form functional synapses by mitochondrial support, accompanied by increased brain-derived neurotrophic factor signaling. Methods Rats were treated for 1 week with vortioxetine or fluoxetine at pharmacologically relevant doses. Number of synapses and mitochondria in hippocampus CA1 were quantified by electron microscopy. Brain-derived neurotrophic factor protein levels were visualized with immunohistochemistry. Gene and protein expression of synapse and mitochondria-related markers were investigated with real-time quantitative polymerase chain reaction and immunoblotting. Results Vortioxetine increased number of synapses and mitochondria significantly, whereas fluoxetine had no effect after 1-week dosing. BDNF levels in hippocampus DG and CA1 were significantly higher after vortioxetine treatment. Gene expression levels of Rac1 after vortioxetine treatment were significantly increased. There was a tendency towards increased gene expression levels of Drp1 and protein levels of Rac1. However, both gene and protein levels of c-Fos were significantly decreased. Furthermore, there was a significant positive correlation between BDNF levels and mitochondria and synapse numbers. Conclusion Our results imply that mitochondria play a critical role in synaptic plasticity accompanied by increased BDNF levels. Rapid changes in BDNF levels and synaptic/mitochondria plasticity of hippocampus following vortioxetine compared with fluoxetine may be ascribed to vortioxetine’s modulation of serotonin receptors. PMID

Cloning and expression of the rat homologue of the Huntington disease gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmitt, I.; Epplen, J.T.; Riess, O.

1994-09-01

Huntington`s disease (HD) is an autosomal dominant neurodegenerative disorder which is manifested usually in adult life. The age of onset is variable and leads to progressive symptoms including involuntary choreatic movements and various cognitive and psychiatric disturbances. Recently, a gene (IT15) was cloned containing a (CAG){sub n} repeat which is elongated and unstable in HD patients. IT15 is widely expressed in human tissues but unrelated to any known deduced protein sequence. To further investigate the HD gene, 15 rat cDNA libraries were screened. 24 clones have been identified covering the Huntingtin gene. Comparison of the Huntingtin gene between human andmore » rat revealed homologies between 80% and 87% at the DNA level and about 90% at the protein level. These analyses will help to define biologically important sequence regions, e.g., via evolutionary conservation. One clone contains the (CAG){sub n} repeat which consists of eight triplets compared to seven triplets in the mouse and a median of 17 in human. As in humans there are two transcripts arising from differential 3{prime}-polyadenylation. In the 3{prime}UTR a stretch of about 280 bp is exchanged for a 250 bp fragment with no homology in rodents and man. The cDNA clones are currently used to study Huntingtin gene expression during development in rodent tissues. RNA in situ hybridization of embryonic sections shows predominant signals in all neuronal tissues. In contrast to previously published data Huntingtin mRNA expression in testis is increased in spermatocytes vs. spermatogonia.« less

Brain-Derived Neurotrophic Factor (BDNF) protein levels in anxiety disorders: systematic review and meta-regression analysis

PubMed Central

Suliman, Sharain; Hemmings, Sian M. J.; Seedat, Soraya

2013-01-01

Background: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that is involved in the synaptic plasticity and survival of neurons. BDNF is believed to be involved in the pathogenesis of several neuropsychiatric disorders. As findings of BDNF levels in anxiety disorders have been inconsistent, we undertook to conduct a systematic review and meta-analysis of studies that assessed BDNF protein levels in these disorders. Methods: We conducted the review using electronic databases and searched reference lists of relevant articles for any further studies. Studies that measured BDNF protein levels in any anxiety disorder and compared these to a control group were included. Effect sizes of the differences in BDNF levels between anxiety disorder and control groups were calculated. Results: Eight studies with a total of 1179 participants were included. Initial findings suggested that BDNF levels were lower in individuals with any anxiety disorder compared to those without [Standard Mean Difference (SMD) = −0.94 (−1.75, −0.12), p ≤ 0.05]. This was, however, dependent on source of BDNF protein [plasma: SMD = −1.31 (−1.69, −0.92), p ≤ 0.01; serum: SMD = −1.06 (−2.27, 0.16), p ≥ 0.01] and type of anxiety disorder [PTSD: SMD = −0.05 (−1.66, 1.75), p ≥ 0.01; OCD: SMD = −2.33 (−4.21, −0.45), p ≤ 0.01]. Conclusion: Although BDNF levels appear to be reduced in individuals with an anxiety disorder, this is not consistent across the various anxiety disorders and may largely be explained by the significantly lowered BDNF levels found in OCD. Results further appear to be mediated by differences in sampling methods. Findings are, however, limited by the lack of research in this area, and given the potential for BDNF as a biomarker of anxiety disorders, it would be useful to clarify the relationship further. PMID:23908608

Inactivation of the Huntington's disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo

PubMed Central

Woda, Juliana M; Calzonetti, Teresa; Hilditch-Maguire, Paige; Duyao, Mabel P; Conlon, Ronald A; MacDonald, Marcy E

2005-01-01

Background Huntingtin, the HD gene encoded protein mutated by polyglutamine expansion in Huntington's disease, is required in extraembryonic tissues for proper gastrulation, implicating its activities in nutrition or patterning of the developing embryo. To test these possibilities, we have used whole mount in situ hybridization to examine embryonic patterning and morphogenesis in homozygous Hdhex4/5 huntingtin deficient embryos. Results In the absence of huntingtin, expression of nutritive genes appears normal but E7.0–7.5 embryos exhibit a unique combination of patterning defects. Notable are a shortened primitive streak, absence of a proper node and diminished production of anterior streak derivatives. Reduced Wnt3a, Tbx6 and Dll1 expression signify decreased paraxial mesoderm and reduced Otx2 expression and lack of headfolds denote a failure of head development. In addition, genes initially broadly expressed are not properly restricted to the posterior, as evidenced by the ectopic expression of Nodal, Fgf8 and Gsc in the epiblast and T (Brachyury) and Evx1 in proximal mesoderm derivatives. Despite impaired posterior restriction and anterior streak deficits, overall anterior/posterior polarity is established. A single primitive streak forms and marker expression shows that the anterior epiblast and anterior visceral endoderm (AVE) are specified. Conclusion Huntingtin is essential in the early patterning of the embryo for formation of the anterior region of the primitive streak, and for down-regulation of a subset of dynamic growth and transcription factor genes. These findings provide fundamental starting points for identifying the novel cellular and molecular activities of huntingtin in the extraembryonic tissues that govern normal anterior streak development. This knowledge may prove to be important for understanding the mechanism by which the dominant polyglutamine expansion in huntingtin determines the loss of neurons in Huntington's disease. PMID:16109169

Inactivation of the Huntington's disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo.

PubMed

Woda, Juliana M; Calzonetti, Teresa; Hilditch-Maguire, Paige; Duyao, Mabel P; Conlon, Ronald A; MacDonald, Marcy E

2005-08-18

Huntingtin, the HD gene encoded protein mutated by polyglutamine expansion in Huntington's disease, is required in extraembryonic tissues for proper gastrulation, implicating its activities in nutrition or patterning of the developing embryo. To test these possibilities, we have used whole mount in situ hybridization to examine embryonic patterning and morphogenesis in homozygous Hdh(ex4/5) huntingtin deficient embryos. In the absence of huntingtin, expression of nutritive genes appears normal but E7.0-7.5 embryos exhibit a unique combination of patterning defects. Notable are a shortened primitive streak, absence of a proper node and diminished production of anterior streak derivatives. Reduced Wnt3a, Tbx6 and Dll1 expression signify decreased paraxial mesoderm and reduced Otx2 expression and lack of headfolds denote a failure of head development. In addition, genes initially broadly expressed are not properly restricted to the posterior, as evidenced by the ectopic expression of Nodal, Fgf8 and Gsc in the epiblast and T (Brachyury) and Evx1 in proximal mesoderm derivatives. Despite impaired posterior restriction and anterior streak deficits, overall anterior/posterior polarity is established. A single primitive streak forms and marker expression shows that the anterior epiblast and anterior visceral endoderm (AVE) are specified. Huntingtin is essential in the early patterning of the embryo for formation of the anterior region of the primitive streak, and for down-regulation of a subset of dynamic growth and transcription factor genes. These findings provide fundamental starting points for identifying the novel cellular and molecular activities of huntingtin in the extraembryonic tissues that govern normal anterior streak development. This knowledge may prove to be important for understanding the mechanism by which the dominant polyglutamine expansion in huntingtin determines the loss of neurons in Huntington's disease.

BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus.

PubMed

Bukalo, Olena; Lee, Philip R; Fields, R Douglas

2016-12-02

Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation. Published by Elsevier Ireland Ltd.

Role of proBDNF and BDNF in dendritic spine plasticity and depressive-like behaviors induced by an animal model of depression.

PubMed

Qiao, Hui; An, Shu-Cheng; Xu, Chang; Ma, Xin-Ming

2017-05-15

Major depressive disorder (MDD) is one of the most common psychiatric disorder, but the underlying mechanisms are largely unknown. Increasing evidence shows that brain-derived neurotrophic factor (BDNF) plays an important role in the structural plasticity induced by depression. Considering the opposite effects of BDNF and its precursor proBDNF on neural plasticity, we hypothesized that the balance of BDNF and proBDNF plays a critical role in chronic unpredicted mild stress (CUMS)-induced depressive-like behaviors and structural plasticity in the rodent hippocampus. The aims of this study were to compare the functions of BDNF and proBDNF in the CUMS-induced depressive-like behaviors, and determine the effects of BDNF and proBDNF on expressions of kalirin-7, postsynaptic density protein 95 (PSD95) and NMDA receptor subunit NR2B in the hippocampus of stressed and naïve control rats, respectively. Our results showed that CUMS induced depressive-like behaviors, caused a decrease in the ratio of BDNF/proBDNF in the hippocampus and resulted in a reduction in spine density in hippocampal CA1 pyramidal neurons; these alterations were accompanied by a decrease in the levels of kalirin-7, PSD95 and NR2B in the hippocampus. Injection of exogenous BDNF into the CA1 area of stressed rats reversed CUMS-induced depressive-like behaviors and prevented CUMS-induced spine loss and decrease in kalirin-7, NR2B and PSD95 levels. In contrast, injection of exogenous proBDNF into the CA1 region of naïve rats caused depressive-like behavior and an accompanying decrease in both spine density and the levels of kalirin-7, NR2B and PSD95. Taken together, our results suggest that the ratio of BDNF to proBDNF in the hippocampus plays a key role in CUMS-induced depressive-like behaviors and alterations of dendritic spines in hippocampal CA1 pyramidal neurons. Kalirin-7 may play an important role during this process. Copyright © 2017 Elsevier B.V. All rights reserved.

Variant BDNF (Val66Met) polymorphism contributes to developmental and estrous-stage-specific expression of anxiety-like behavior in female mice

PubMed Central

Bath, Kevin G.; Chuang, Jocelyn; Spencer-Segal, Joanna L.; Amso, Dima; Altemus, Margaret; McEwen, Bruce S.; Lee, Francis S.

2012-01-01

Background Most anxiety and depressive disorders are twice as common in women compared to men and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and peri-menopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Val66Met), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Approach As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle specific expression of anxiety-like behaviors. Results Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and as adults differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle, specifically more anxiety-like behaviors during the estrus phase. Conclusions These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans. PMID:22552045

Methylation of BDNF in women with bulimic eating syndromes: associations with childhood abuse and borderline personality disorder.

PubMed

Thaler, Lea; Gauvin, Lise; Joober, Ridha; Groleau, Patricia; de Guzman, Rosherrie; Ambalavanan, Amirthagowri; Israel, Mimi; Wilson, Samantha; Steiger, Howard

2014-10-03

DNA methylation allows for the environmental regulation of gene expression and is believed to link environmental stressors to such mental-illness phenotypes as eating disorders. Numerous studies have shown an association between bulimia nervosa (BN) and variations in brain-derived neurotrophic factor (BDNF). BDNF has also been linked to borderline personality disorder (BPD) and to such traits as reward dependence. We examined the extent to which BDNF methylation corresponded to bulimic or normal-eater status, and also to the presence of comorbid borderline personality disorder (BPD) and childhood abuse. Our sample consisted of 64 women with BN and 32 normal-eater (NE) control women. Participants were assessed for eating-disorder symptoms, comorbid psychopathology, and childhood trauma, and then they were required to provide blood samples for methylation analyses. We observed a significant site×group (BN vs. NE) interaction indicating that women with BN showed increases in methylation at specific regions of the BDNF promoter. Furthermore, examining effects of childhood abuse and BPD, we observed significant site×group interactions such that groups composed of individuals with childhood abuse or BPD had particularly high levels of methylation at selected CpG sites. Our findings suggest that BN, especially when co-occurring with childhood abuse or BPD, is associated with a propensity towards elevated methylation at specific BDNF promoter region sites. These findings imply that hypermethylation of the BDNF gene may be related to eating disorder status, developmental stress exposure, and comorbid psychopathology. Copyright © 2014 Elsevier Inc. All rights reserved.

Suicide attempt, clinical correlates, and BDNF Val66Met polymorphism in chronic patients with schizophrenia.

PubMed

Xia, Haisen; Zhang, Guangya; Du, Xiangdong; Zhang, Yingyang; Yin, Guangzhong; Dai, Jing; He, Man-Xi; Soares, Jair C; Li, Xiaosi; Zhang, Xiang Yang

2018-02-01

Recent evidence suggests the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of suicidal behavior. Because schizophrenia patients usually have high suicide rates and numerous studies have suggested that BDNF may contribute to the psychopathology of schizophrenia, we hypothesized that the functional polymorphism of BDNF (Val66Met) was associated with suicide attempts in patients with schizophrenia in a Chinese Han population. This polymorphism was genotyped in 825 chronic schizophrenia patients with (n = 123) and without (n = 702) suicide attempts and 445 healthy controls without a history of suicide attempts using a case-control design. The schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale. There were no significant differences in BDNF Val66Met genotype and allele distributions between the patients and healthy controls. However, we found the Val allele (p = .023) and the Val/Val genotypes (p = .058) to be associated with a history of suicide attempts. Moreover, some clinical characteristics, including age and cigarettes smoked each day, interacted with the BDNF gene variant and appeared to play an important role in suicide attempts among schizophrenia patients. The BDNF Val66Met polymorphism itself and its interaction with some clinical variables may influence suicide attempts among schizophrenia patients. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro

PubMed Central

Trushina, Eugenia; Dyer, Roy B.; Badger, John D.; Ure, Daren; Eide, Lars; Tran, David D.; Vrieze, Brent T.; Legendre-Guillemin, Valerie; McPherson, Peter S.; Mandavilli, Bhaskar S.; Van Houten, Bennett; Zeitlin, Scott; McNiven, Mark; Aebersold, Ruedi; Hayden, Michael; Parisi, Joseph E.; Seeberg, Erling; Dragatsis, Ioannis; Doyle, Kelly; Bender, Anna; Chacko, Celin; McMurray, Cynthia T.

2004-01-01

Recent data in invertebrates demonstrated that huntingtin (htt) is essential for fast axonal trafficking. Here, we provide direct and functional evidence that htt is involved in fast axonal trafficking in mammals. Moreover, expression of full-length mutant htt (mhtt) impairs vesicular and mitochondrial trafficking in mammalian neurons in vitro and in whole animals in vivo. Particularly, mitochondria become progressively immobilized and stop more frequently in neurons from transgenic animals. These defects occurred early in development prior to the onset of measurable neurological or mitochondrial abnormalities. Consistent with a progressive loss of function, wild-type htt, trafficking motors, and mitochondrial components were selectively sequestered by mhtt in human Huntington's disease-affected brain. Data provide a model for how loss of htt function causes toxicity; mhtt-mediated aggregation sequesters htt and components of trafficking machinery leading to loss of mitochondrial motility and eventual mitochondrial dysfunction. PMID:15340079

Accommodation of structural rearrangements in the huntingtin-interacting protein 1 coiled-coil domain.

PubMed

Wilbur, Jeremy D; Hwang, Peter K; Brodsky, Frances M; Fletterick, Robert J

2010-03-01

Huntingtin-interacting protein 1 (HIP1) is an important link between the actin cytoskeleton and clathrin-mediated endocytosis machinery. HIP1 has also been implicated in the pathogenesis of Huntington's disease. The binding of HIP1 to actin is regulated through an interaction with clathrin light chain. Clathrin light chain binds to a flexible coiled-coil domain in HIP1 and induces a compact state that is refractory to actin binding. To understand the mechanism of this conformational regulation, a high-resolution crystal structure of a stable fragment from the HIP1 coiled-coil domain was determined. The flexibility of the HIP1 coiled-coil region was evident from its variation from a previously determined structure of a similar region. A hydrogen-bond network and changes in coiled-coil monomer interaction suggest that the HIP1 coiled-coil domain is uniquely suited to allow conformational flexibility.

BDNF promotes the growth of human neurons through crosstalk with the Wnt/β-catenin signaling pathway via GSK-3β.

PubMed

Yang, Jin-Wei; Ru, Jin; Ma, Wei; Gao, Yan; Liang, Zhang; Liu, Jia; Guo, Jian-Hui; Li, Li-Yan

2015-12-01

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal growth; however, the downstream regulatory mechanisms remain unclear. In this study, we investigated whether BDNF exerts its neurotrophic effects through the Wnt/β-catenin signaling pathway in human embryonic spinal cord neurons in vitro. We found that neuronal growth (soma size and average neurite length) was increased by transfection with a BDNF overexpression plasmid. Western blotting and real-time quantitative PCR showed that expression of the BDNF pathway components TrkB, PI3K, Akt and PLC-γ was increased by BDNF overexpression. Furthermore, the Wnt signaling factors Wnt, Frizzled and Dsh and the downstream target β-catenin were upregulated, whereas GSK-3β was downregulated. In contrast, when BDNF signaling was downregulated with BDNF siRNA, the growth of neurons was decreased. Furthermore, BDNF signaling factors, Wnt pathway components and β-catenin were all downregulated, whereas GSK-3β was upregulated. This suggests that BDNF affects the growth of neurons in vitro through crosstalk with Wnt signaling, and that GSK-3β may be a critical factor linking these two pathways. To evaluate this possibility, we treated neurons with 6-bromoindirubin-3'-oxime (BIO), a small molecule GSK-3β inhibitor. BIO reduced the effects of BDNF upregulation/downregulation on soma size and average neurite length, and suppressed the impact of BDNF modulation on the Wnt signaling pathway. Taken together, our findings suggest that BDNF promotes the growth of neurons in vitro through crosstalk with the Wnt/β-catenin signaling pathway, and that this interaction may be mediated by GSK-3β. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neurogenesis Inhibition Prevents Enriched Environment to Prolong and Strengthen Social Recognition Memory, But Not to Increase BDNF Expression.

PubMed

Pereira-Caixeta, Ana Raquel; Guarnieri, Leonardo O; Pena, Roberta R; Dias, Thomáz L; Pereira, Grace Schenatto

2017-07-01

Hippocampus-dependent memories, such as social recognition (SRM), are modulated by neurogenesis. However, the precise role of newborn neurons in social memory processing is still unknown. We showed previously that 1 week of enriched environment (EE) is sufficient to increase neurogenesis in the hippocampus (HIP) and the olfactory bulb (OB) of mice. Here, we tested the hypothesis that 1 week of EE would enhance SRM persistence and strength. In addition, as brain-derived neurotrophic factor (BDNF) may mediate some of the neurogenesis effects on memory, we also tested if 1 week of EE would increase BDNF expression in the HIP and OB. We also predicted that neurogenesis inhibition would block the gain of function caused by EE on both SRM and BDNF expression. We found that EE increased BDNF expression in the HIP and OB of mice; at the same time, it allowed SRM to last longer. In addition, mice on EE had their SRM unaffected by memory consolidation interferences. As we predicted, treatment with the anti-mitotic drug AraC blocked EE effects on SRM. Surprisingly, neurogenesis inhibition did not affect the BDNF expression, increased by EE. Together, our results suggest that newborn neurons improve SRM persistence through a BDNF-independent mechanism. Interestingly, this study on social memory uncovered an unexpected dissociation between the effect of adult neurogenesis and BDNF expression on memory persistence, reassuring the idea that not all neurogenesis effects on memory are BDNF-dependent.

The Interacting Effect of the BDNF Val66Met Polymorphism and Stressful Life Events on Adolescent Depression Is Not an Artifact of Gene-Environment Correlation: Evidence from a Longitudinal Twin Study

ERIC Educational Resources Information Center

Chen, Jie; Li, Xinying; McGue, Matt

2013-01-01

Background: Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G × E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the…

Effects of acute voluntary loaded wheel running on BDNF expression in the rat hippocampus.

PubMed

Lee, Minchul; Soya, Hideaki

2017-12-31

Voluntary loaded wheel running involves the use of a load during a voluntary running activity. A muscle-strength or power-type activity performed at a relatively high intensity and a short duration may cause fewer apparent metabolic adaptations but may still elicit muscle fiber hypertrophy. This study aimed to determine the effects of acute voluntary wheel running with an additional load on brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus. Ten-week old male Wistar rats were assigned randomly to a (1) sedentary (Control) group; (2) voluntary exercise with no load (No-load) group; or (3) voluntary exercise with an additional load (Load) group for 1-week (acute period). The expression of BDNF genes was quantified by real-time PCR. The average distance levels were not significantly different in the No-load and Load groups. However, the average work levels significantly increased in the Load group. The relative soleus weights were greater in the No-load group. Furthermore, loaded wheel running up-regulated the BDNF mRNA level compared with that in the Control group. The BDNF mRNA levels showed a positive correlation with workload levels (r=0.75), suggesting that the availability of multiple workload levels contributes to the BDNF-related benefits of loaded wheel running noted in this study. This novel approach yielded the first set of findings showing that acute voluntary loaded wheel running, which causes muscular adaptation, enhanced BDNF expression, suggesting a possible role of high-intensity short-term exercise in hippocampal BDNF activity. ©2017 The Korean Society for Exercise Nutrition

Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits.

PubMed

Frustaci, Alessandra; Pozzi, Gino; Gianfagna, Francesco; Manzoli, Lamberto; Boccia, Stefania

2008-01-01

Brain-derived neurotrophic factor (BDNF) is potentially involved in the pathogenesis of anxiety. We carried out meta-analyses to evaluate the relationship between the BDNF Val66Met (valine, methionine) polymorphism and anxiety disorders (AD) or anxiety-related personality traits (ARPT). Medline, Embase and PsycINFO were searched up to December 2007. We investigated 3 outcomes related to BDNF Val66Met polymorphisms: (1) clinically diagnosed cases of AD; (2) ARPT in subjects without psychiatric diagnoses, assessed either by the Neuroticism scale of NEO-Personality Inventory forms (NEO-PI, NEO-PI-R, NEO-FFI), or by (3) the Harm Avoidance (HA) scale of Tridimensional Personality Questionnaire (TPQ) or its extended version Temperament and Character Inventory (TCI). Seven case-control studies were selected for AD, including 1,092 cases and 8,394 controls, while 5 cross-sectional studies for Neuroticism (n = 1,633) and 4 for HA (n = 607). Both Met/Met and Val/Met individuals, as compared to Val/Val, showed a statistically significant lower Neuroticism score [SMD = -0.24 (95% CI: -0.44, -0.04), and -0.11 (95% CI: -0.22, -0.01), respectively]. No significant association was found between BDNF Val66Met polymorphism and AD [OR = 1.13 (95% CI: 0.85-1.52) for Met/Met versus Val/Val] or HA [SMD = 0.11 (95% CI: -0.19, 0.42) for Met/Met vs. Val/Val]. The low number of studies on this topic and their limited sample size, along with the inner limits in the definition of anxiety phenotypes, suggest caution in the interpretation of these results. Larger additional studies possibly investigating the interaction with other genes and environmental exposures are required to confirm these results. 2008 S. Karger AG, Basel.

Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

PubMed

Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A

2012-04-01

The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

NMDA receptor function and NMDA receptor-dependent phosphorylation of huntingtin is altered by the endocytic protein HIP1.

PubMed

Metzler, Martina; Gan, Lu; Wong, Tak Pan; Liu, Lidong; Helm, Jeffrey; Liu, Lili; Georgiou, John; Wang, Yushan; Bissada, Nagat; Cheng, Kevin; Roder, John C; Wang, Yu Tian; Hayden, Michael R

2007-02-28

Huntingtin-interacting protein 1 (HIP1) is an endocytic adaptor protein that plays a role in clathrin-mediated endocytosis and the ligand-induced internalization of AMPA receptors (AMPARs) (Metzler et al., 2003). In the present study, we investigated the role of HIP1 in NMDA receptor (NMDAR) function by analyzing NMDA-dependent transport and NMDA-induced excitotoxicity in neurons from HIP1-/- mice. HIP1 colocalizes with NMDARs in hippocampal and cortical neurons and affinity purifies with NMDARs by GST (glutathione S-transferase) pull down and coimmunoprecipitation. A profound decrease in NMDA-induced AMPAR internalization of 75% occurs in neurons from HIP1-/- mice compared with wild type, using a quantitative single-cell-based internalization assay. This defect in NMDA-dependent removal of surface AMPARs is in agreement with the observed defect in long-term depression induction in hippocampal brain slices of HIP1-/- mice and supports a role of HIP1 in AMPAR internalization in vivo. HIP1-/- neurons are partially protected from NMDA-induced excitotoxicity as assessed by LDH (lactate dehydrogenase) release, TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling) and caspase-3 activation assays, which points to a role of HIP1 in NMDA-induced cell death. Interestingly, phosphorylation of Akt and its substrate huntingtin (htt) decreases during NMDA-induced excitotoxicity by 48 and 31%, respectively. This decrease is significantly modulated by HIP1, resulting in 94 and 48% changes in P-Akt and P-htt levels in HIP1-/- neurons, respectively. In summary, we have shown that HIP1 influences important NMDAR functions and that both HIP1 and htt participate in NMDA-induced cell death. These findings may provide novel insights into the cellular mechanisms underlying enhanced NMDA-induced excitotoxicity in Huntington's disease.

Repetitive stress leads to impaired cognitive function that is associated with DNA hypomethylation, reduced BDNF and a dysregulated HPA axis.

PubMed

Makhathini, Khayelihle B; Abboussi, Oualid; Stein, Dan J; Mabandla, Musa V; Daniels, William M U

2017-08-01

Exposure to repetitive stress has a negative influence on cognitive-affective functioning, with growing evidence that these effects may be mediated by a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, abnormal neurotrophic factor levels and its subsequent impact on hippocampal function. However, there are few data about the effect of repetitive stressors on epigenetic changes in the hippocampus. In the present study, we examine how repetitive restrain stress (RRS) affects cognitive-affective functioning, HPA axis regulation, brain-derived neurotrophic factor (BDNF) levels, and global hippocampal DNA methylation. RRS was induced in rats by restraining the animals for 6h per day for 28 days. The novel object recognition test (NORT) was used to assess cognitive functioning and the open field test (OFT) was performed to assess anxiety-like behavior during the last week of stress. Hippocampal BDNF levels, glucocorticoid (GR) and mineralocorticoid (MR) receptor mRNA were assessed using real-time PCR and confirmed with Western blot, while ELISAs were used to determine plasma corticosterone levels and the global methylation status of the hippocampus. Animals exposed to repetitive stress demonstrated significant alterations in the NORT and OFT, had significantly increased plasma corticosterone and significantly decreased hippocampal BDNF concentrations. The expression levels of GR and MR mRNA and protein levels of these genes were significantly decreased in the stressed group compared to control animals. The global DNA methylation of the hippocampal genome of stressed animals was also significantly decreased compared to controls. The data here are consistent with previous work emphasizing the role of the HPA axis and neurotrophic factors in mediating cognitive-affective changes after exposure to repetitive stressors. Our findings, however, extend the literature by indicating that epigenetic alterations in the hippocampal genome may also play an important role in the

Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction.

PubMed

Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V; Will, Nathan E; Irmady, Krithi; Lee, Francis S; Hempstead, Barbara L; Bracken, Clay

2013-01-01

A common single-nucleotide polymorphism (SNP) in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This SNP is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism, we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75(NTR) and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand, which modulates neuronal morphology.

Val66Met Polymorphism of BDNF Alters Prodomain Structure to Induce Neuronal Growth Cone Retraction

PubMed Central

Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V.; Will, Nathan E.; Irmady, Krithi; Lee, Francis S.; Hempstead, Barbara L.; Bracken, Clay

2013-01-01

A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene results in a Val66Met substitution in the BDNF prodomain region. This single-nucleotide polymorphism is associated with alterations in memory and with enhanced risk to develop depression and anxiety disorders in humans. Here we show that the isolated BDNF prodomain is detected in the hippocampus and that it can be secreted from neurons in an activity-dependent manner. Using nuclear magnetic resonance spectroscopy and circular dichroism we find that the prodomain is intrinsically disordered, and the Val66Met substitution induces structural changes. Surprisingly, application of Met66 (but not Val66) BDNF prodomain induces acute growth cone retraction and a decrease in Rac activity in hippocampal neurons. Expression of p75NTR and differential engagement of the Met66 prodomain to the SorCS2 receptor are required for this effect. These results identify the Met66 prodomain as a new active ligand which modulates neuronal morphology. PMID:24048383

Free-Energy Landscape of the Amino-Terminal Fragment of Huntingtin in Aqueous Solution.

PubMed

Binette, Vincent; Côté, Sébastien; Mousseau, Normand

2016-03-08

The first exon of Huntingtin-a protein with multiple biological functions whose misfolding is related to Huntington's disease-modulates its localization, aggregation, and function within the cell. It is composed of a 17-amino-acid amphipathic segment (Htt17), an amyloidogenic segment of consecutive glutamines (QN), and a proline-rich segment. Htt17 is of fundamental importance: it serves as a membrane anchor to control the localization of huntingtin, it modulates huntingtin's function through posttranslational modifications, and it controls the self-assembly of the amyloidogenic QN segment into oligomers and fibrils. Experimentally, the conformational ensemble of the Htt17 monomer, as well as the impact of the polyglutamine and proline-rich segments, remains, however, mostly uncharacterized at the atomic level due to its intrinsic flexibility. Here, we unveil the free-energy landscape of Htt17, Htt17Q17, and Htt17Q17P11 using Hamiltonian replica exchange combined with well-tempered metadynamics. We characterize the free-energy landscape of these three fragments in terms of a few selected collective variables. Extensive simulations reveal that the free energy of Htt17 is dominated by a broad ensemble of configurations that agree with solution NMR chemical shifts. Addition of Q17 at its carboxy-terminus reduces the extent of the main basin to more extended configurations of Htt17 with lower helix propensity. Also, the aliphatic carbons of Q17 partially sequester the nonpolar amino acids of Htt17. For its part, addition of Q17P11 shifts the overall landscape to a more extended and helical Htt17 stabilized by interactions with Q17 and P11, which almost exclusively form a PPII-helix, as well as by intramolecular H-bonds and salt bridges. Our characterization of Huntingtin's amino-terminus provides insights into the structural origin of its ability to oligomerize and interact with phospholipid bilayers, processes closely linked to the biological functions of this protein

Huntingtin interacting protein 1 is a novel brain tumor marker that associates with epidermal growth factor receptor.

PubMed

Bradley, Sarah V; Holland, Eric C; Liu, Grace Y; Thomas, Dafydd; Hyun, Teresa S; Ross, Theodora S

2007-04-15

Huntingtin interacting protein 1 (HIP1) is a multidomain oncoprotein whose expression correlates with increased epidermal growth factor receptor (EGFR) levels in certain tumors. For example, HIP1-transformed fibroblasts and HIP1-positive breast cancers have elevated EGFR protein levels. The combined association of HIP1 with huntingtin, the protein that is mutated in Huntington's disease, and the known overexpression of EGFR in glial brain tumors prompted us to explore HIP1 expression in a group of patients with different types of brain cancer. We report here that HIP1 is overexpressed with high frequency in brain cancers and that this overexpression correlates with EGFR and platelet-derived growth factor beta receptor expression. Furthermore, serum samples from patients with brain cancer contained anti-HIP1 antibodies more frequently than age-matched brain cancer-free controls. Finally, we report that HIP1 physically associates with EGFR and that this association is independent of the lipid, clathrin, and actin interacting domains of HIP1. These findings suggest that HIP1 may up-regulate or maintain EGFR overexpression in primary brain tumors by directly interacting with the receptor. This novel HIP1-EGFR interaction may work with or independent of HIP1 modulation of EGFR degradation via clathrin-mediated membrane trafficking pathways. Further investigation of HIP1 function in brain cancer biology and validation of its use as a prognostic or predictive brain tumor marker are now warranted.

The role of the BDNF Val66Met polymorphism in individual differences in long-term memory capacity.

PubMed

Montag, Christian; Felten, Andrea; Markett, Sebastian; Fischer, Luise; Winkel, Katja; Cooper, Andrew; Reuter, Martin

2014-12-01

The protein brain-derived neurotrophic factor (BDNF) plays an important role in diverse memory processes and is strongly expressed in the hippocampus. The hippocampus itself is a key structure involved in the processing of information from short-term to long-term memory. Due to the putative role of BDNF in memory consolidation, a prominent single nucleotide polymorphism (SNP) on the BDNF gene (BDNF Val66Met) was investigated in the context of long-term memory performance. N=138 students were presented with 40 words from 10 categories, each consisting of eight words such as 'fruits' or 'vehicles' in a memory recognition task (specifically the Deese-Roediger-McDermott Paradigm). Recognition performance was analyzed 25 min after the initial presentation of the word list and subsequently 1 week after the initial presentation. Overall, individual long-term memory performance immediately after learning the word list (T1) and performance 1 week later (T2) did not differ on the basis of the BDNF SNP, but an interaction effect of BDNF Val66Met by time-of-recall was found: Carriers of the Met66+ variant showed the strongest decline in hit rate performance over time.

Reduced cortical BDNF expression and aberrant memory in Carf knockout mice

PubMed Central

McDowell, Kelli A.; Hutchinson, Ashley N.; Wong-Goodrich, Sarah J.E.; Presby, Matthew M.; Su, Dan; Rodriguiz, Ramona M.; Law, Krystal C.; Williams, Christina L.; Wetsel, William C.; West, Anne E.

2010-01-01

Transcription factors are a key point of convergence between the cell-intrinsic and extracellular signals that guide synaptic development and brain plasticity. Calcium-Response Factor (CaRF) is a unique transcription factor first identified as a binding protein for a calcium-response element in the gene encoding Brain-Derived Neurotrophic Factor (Bdnf). We have now generated Carf knockout (KO) mice to characterize the function of this factor in vivo. Intriguingly, Carf KO mice have selectively reduced expression of Bdnf exon IV-containing mRNA transcripts and BDNF protein in the cerebral cortex while BDNF levels in the hippocampus and striatum remain unchanged, implicating CaRF as a brain region-selective regulator of BDNF expression. At the cellular level, Carf KO mice show altered expression of GABAergic proteins at striatal synapses, raising the possibility that CaRF may contribute to aspects of inhibitory synapse development. Carf KO mice show normal spatial learning in the Morris water maze and normal context-dependent fear conditioning. However they have an enhanced ability to find a new platform location on the first day of reversal training in the water maze and they extinguish conditioned fear more slowly than their wildtype (WT) littermates. Finally, Carf KO mice show normal short-term and long-term memory in a novel object recognition task, but exhibit impairments during the remote memory phase of testing. Taken together these data reveal novel roles for CaRF in the organization and/or function of neural circuits that underlie essential aspects of learning and memory. PMID:20519520

Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury.

PubMed

Wurzelmann, Mary; Romeika, Jennifer; Sun, Dong

2017-01-01

Traumatic brain injury (TBI) is a major health problem worldwide. Following primary mechanical insults, a cascade of secondary injuries often leads to further neural tissue loss. Thus far there is no cure to rescue the damaged neural tissue. Current therapeutic strategies primarily target the secondary injuries focusing on neuroprotection and neuroregeneration. The neurotrophin brain-derived neurotrophic factor (BDNF) has significant effect in both aspects, promoting neuronal survival, synaptic plasticity and neurogenesis. Recently, the flavonoid 7,8-dihydroxyflavone (7,8-DHF), a small TrkB agonist that mimics BDNF function, has shown similar effects as BDNF in promoting neuronal survival and regeneration following TBI. Compared to BDNF, 7,8-DHF has a longer half-life and much smaller molecular size, capable of penetrating the blood-brain barrier, which makes it possible for non-invasive clinical application. In this review, we summarize functions of the BDNF/TrkB signaling pathway and studies examining the potential of BDNF and 7,8-DHF as a therapy for TBI.

SorCS2 is required for BDNF-dependent plasticity in the hippocampus.

PubMed

Glerup, S; Bolcho, U; Mølgaard, S; Bøggild, S; Vaegter, C B; Smith, A H; Nieto-Gonzalez, J L; Ovesen, P L; Pedersen, L F; Fjorback, A N; Kjolby, M; Login, H; Holm, M M; Andersen, O M; Nyengaard, J R; Willnow, T E; Jensen, K; Nykjaer, A

2016-12-01

SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75 NTR , required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75 NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2 -/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75 NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.

Multiple faces of BDNF in cocaine addiction

PubMed Central

Li, Xuan; Wolf, Marina E.

2014-01-01

Brain-derived neurotrophic factor (BDNF) has been found to play roles in many types of plasticity including drug addiction. Here we focus on rodent studies over the past two decades that have demonstrated diverse roles of BDNF in models of cocaine addiction. First, we will provide an overview of studies showing that cocaine exposure alters (and generally increases) BDNF levels in reward-related regions including the ventral tegmental area, nucleus accumbens, prefrontal cortex, and amygdala. Then we will review evidence that BDNF contributes to behavioral changes in animal models of cocaine addiction, focusing on conditioned place preference, behavioral sensitization, maintenance and reinstatement of self-administration, and incubation of cocaine craving. Last, we will review the role of BDNF in synaptic plasticity, particularly as it relates to plasticity of AMPA receptor transmission after cocaine exposure. We conclude that BDNF regulates cocaine-induced behaviors in a highly complex manner that varies depending on the brain region (and even among different cell types within the same brain region), the nature of cocaine exposure, and the “addiction phase” examined (e.g., acquisition vs maintenance; early vs late withdrawal). These complexities make BDNF a daunting therapeutic target for treating cocaine addiction. However, recent clinical evidence suggests that the serum BDNF level may serve as a biomarker in cocaine addicts to predict future relapse, providing an alternative direction for exploring BDNF’s potential relevance to treating cocaine addiction. PMID:25449839

Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression

PubMed Central

Podda, Maria Vittoria; Cocco, Sara; Mastrodonato, Alessia; Fusco, Salvatore; Leone, Lucia; Barbati, Saviana Antonella; Colussi, Claudia; Ripoli, Cristian; Grassi, Claudio

2016-01-01

The effects of transcranial direct current stimulation (tDCS) on brain functions and the underlying molecular mechanisms are yet largely unknown. Here we report that mice subjected to 20-min anodal tDCS exhibited one-week lasting increases in hippocampal LTP, learning and memory. These effects were associated with enhanced: i) acetylation of brain-derived neurotrophic factor (Bdnf) promoter I; ii) expression of Bdnf exons I and IX; iii) Bdnf protein levels. The hippocampi of stimulated mice also exhibited enhanced CREB phosphorylation, pCREB binding to Bdnf promoter I and recruitment of CBP on the same regulatory sequence. Inhibition of acetylation and blockade of TrkB receptors hindered tDCS effects at molecular, electrophysiological and behavioral levels. Collectively, our findings suggest that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene, and support the therapeutic potential of tDCS for brain diseases associated with impaired neuroplasticity. PMID:26908001

Effect of BDNF Val66Met polymorphism on digital working memory and spatial localization in a healthy Chinese Han population.

PubMed

Gong, Pingyuan; Zheng, Anyun; Chen, Dongmei; Ge, Wanhua; Lv, Changchao; Zhang, Kejin; Gao, Xiaocai; Zhang, Fuchang

2009-07-01

Cognitive abilities are complex human traits influenced by genetic factors. Brain-derived neurotrophic factor (BDNF), a unique polypeptide growth factor, has an influence on the differentiation and survival of neurons in the nervous system. A single-nucleotide polymorphism (rs6265) in the human gene, resulting in a valine to methionine substitution in the pro-BDNF protein, was thought to associate with psychiatric disorders and might play roles in the individual difference of cognitive abilities. However, the specific roles of the gene in cognition remain unclear. To investigate the relationships between the substitution and cognitive abilities, a healthy population-based study and the PCR-SSCP method were performed. The results showed the substitution was associated with digital working memory (p = 0.02) and spatial localization (p = 0.03), but not with inhibition, shifting, updating, visuo-spatial working memory, long-term memory, and others (p > 0.05) among the compared genotype groups analyzed by general linear model. On the other hand, the participants with BDNF (GG) had higher average performance in digital working memory and spatial localization than the ones with BDNF (AA). The findings of the present work implied that the variation in BDNF might play positive roles in human digital working memory and spatial localization.

PKA-CREB-BDNF signaling pathway mediates propofol-induced long-term learning and memory impairment in hippocampus of rats.

PubMed

Zhong, Yu; Chen, Jing; Li, Li; Qin, Yi; Wei, Yi; Pan, Shining; Jiang, Yage; Chen, Jialin; Xie, Yubo

2018-04-20

Studies have found that propofol can induce widespread neuroapoptosis in developing brains, which leads to cause long-term learning and memory abnormalities. However, the specific cellular and molecular mechanisms underlying propofol-induced neuroapoptosis remain elusive. The aim of the present study was to explore the role of PKA-CREB-BDNF signaling pathway in propofol-induced long-term learning and memory impairment during brain development. Seven-day-old rats were randomly assigned to control, intralipid and three treatment groups (n = 5). Rats in control group received no treatment. Intralipid (10%, 10 mL/kg) for vehicle control and different dosage of propofol for three treatment groups (50, 100 and 200 mg/kg) were administered intraperitoneally. FJB staining, immunohistochemistry analysis for neuronal nuclei antigen and transmission electron microscopy were used to detect neuronal apoptosis and structure changes. MWM test examines the long-term spatial learning and memory impairment. The expression of PKA, pCREB and BDNF was quantified using western blots. Propofol induced significant increase of FJB-positive cells and decrease of PKA, pCREB and BDNF protein levels in the immature brain of P7 rats. Using the MWM test, propofol-treated rats demonstrated long-term spatial learning and memory impairment. Moreover, hippocampal NeuN-positive cell loss, long-lasting ultrastructural abnormalities of the neurons and synapses, and long-term down-regulation of PKA, pCREB and BDNF protein expression in adult hippocampus were also found. Our results indicated that neonatal propofol exposure can significantly result in long-term learning and memory impairment in adulthood. The possible mechanism involved in the propofol-induced neuroapoptosis was related to down-regulation of PKA-CREB-BDNF signaling pathway. Copyright © 2018. Published by Elsevier B.V.

A common variant near BDNF is associated with dietary calcium intake in adolescents.

PubMed

Dušátková, Lenka; Zamrazilová, Hana; Aldhoon-Hainerová, Irena; Sedláčková, Barbora; Včelák, Josef; Hlavatý, Petr; Bendlová, Běla; Kunešová, Marie; Hainer, Vojtěch

2015-09-01

Specific targets for most obesity candidate genes discovered by genomewide association studies remain unknown. Such genes are often highly expressed in the hypothalamus, indicating their role in energy homeostasis. We aimed to evaluate the associations of selected gene variants with adiposity and dietary traits. Anthropometric parameters, fat mass, dietary intake (total energy, fat, protein, carbohydrate, fiber, and calcium) and 10 gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R and FTO) were analyzed in 1953 Czech individuals aged 10.0 to 18.0 years (1035 nonoverweight and 918 overweight: body mass index [BMI] ≥90th percentile). Obesity risk alleles of TMEM18 rs7561317, SEC16B rs10913469, and FTO rs9939609 were related to increased body weight and BMI (P < .005). The FTO variant also showed a significant positive association with waist circumference and fat mass (P < .001). Overweight adolescents had a lower total energy intake (P < .001) but a higher percentage of fat (P = .009) and protein intake (P < .001) than the nonoverweight subjects. There was also a lower calcium intake in the overweight group (P < .001). An association with at least one component of dietary intake was found in 3 of 10 studied gene variants. The MC4R rs17782313 was associated negatively with protein (P = .012) and positively associated with fiber (P = .032) intakes. The obesity risk alleles of BDNF rs925946 and FTO rs9939609 were related to a lower calcium intake (P = .001 and .037). The effects of FTO and MC4R variants, however, disappeared after corrections for multiple testing. Our results suggest that the common BDNF variant may influence dietary calcium intake independent of BMI. Copyright © 2015 Elsevier Inc. All rights reserved.

The Impact of BDNF Polymorphisms on Suicidality in Treatment-Resistant Major Depressive Disorder: A European Multicenter Study.

PubMed

Schosser, Alexandra; Carlberg, Laura; Calati, Raffaella; Serretti, Alessandro; Massat, Isabel; Spindelegger, Christoph; Linotte, Sylvie; Mendlewicz, Julien; Souery, Daniel; Zohar, Joseph; Montgomery, Stuart; Kasper, Siegfried

2017-10-01

Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results. A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene. Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n=34, 13.6%). Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Relationship Between Hippocampal Volume, Serum BDNF, and Depression Severity Following Electroconvulsive Therapy in Late-Life Depression

PubMed Central

Bouckaert, Filip; Dols, Annemiek; Emsell, Louise; De Winter, François-Laurent; Vansteelandt, Kristof; Claes, Lene; Sunaert, Stefan; Stek, Max; Sienaert, Pascal; Vandenbulcke, Mathieu

2016-01-01

Recent structural imaging studies have described hippocampal volume changes following electroconvulsive therapy (ECT). It has been proposed that serum brain-derived neurotrophic factor (sBDNF)-mediated neuroplasticity contributes critically to brain changes following antidepressant treatment. To date no studies have investigated the relationship between changes in hippocampal volume, mood, and sBDNF following ECT. Here, we combine these measurements in a longitudinal study of severe late-life unipolar depression (LLD). We treated 88 elderly patients with severe LLD twice weekly until remission (Montgomery–Åsberg Depression Rating Scale (MADRS) <10). sBDNF and MADRS were obtained before ECT (T0), after the sixth ECT (T1), 1 week after the last ECT (T2), 4 weeks after the last ECT (T3), and 6 months after the last ECT (T4). Hippocampal volumes were quantified by manual segmentation of 3T structural magnetic resonance images in 66 patients at T0 and T2 and in 23 patients at T0, T2, and T4. Linear mixed models (LMM) were used to examine the evolution of MADRS, sBDNF, and hippocampal volume over time. Following ECT, there was a significant decrease in MADRS scores and a significant increase in hippocampal volume. Hippocampal volume decreased back to baseline values at T4. Compared with T0, sBDNF levels remained unchanged at T1, T2, and T3. There was no coevolution between changes in MADRS scores, hippocampal volume, and sBDNF. Hippocampal volume increase following ECT is an independent neurobiological effect unrelated to sBDNF and depressive symptomatology, suggesting a complex mechanism of action of ECT in LLD. PMID:27272769

Physical therapy intervention (PTI) increases plasma brain-derived neurotrophic factor (BDNF) levels in non-frail and pre-frail elderly women.

PubMed

Coelho, F M; Pereira, D S; Lustosa, L P; Silva, J P; Dias, J M D; Dias, R C D; Queiroz, B Z; Teixeira, A L; Teixeira, M M; Pereira, L S M

2012-01-01

Biomarkers are important factors in the identification of the frail elderly (higher risk of developing disease) and in assessing the impact of PTI. On the other hand, BDNF has been related to neuroprotection in a series of central nervous system diseases in older age. The levels of BDNF in groups of elderly women classified according to Fried phenotype (non-frail and pre-frail) were compared. We assessed the impact of a PTI on BDNF levels. A convenience sample of 48 elderly women was randomly selected. The PTI group was composed by 20 elderly women selected from this group. Plasma neurotrophic factors, such as BDNF, glial-derived neutrophic factor (GDNF), and nerve growth factor (NGF) were measured by enzyme-linked immunosorbent assay (ELISA). Timed-up-and-go (TUG) test, hand-grip and work/body weight were evaluated before and after the intervention. Plasma concentrations of BDNF were significantly higher in non-frail in comparison to pre-frail elderly women. After the PTI, higher levels of BDNF were found in elderly women (before 351±68 pg/ml and after 593±79 pg/ml; p<0.001). Both groups had an increase in BDNF levels after the PTI. The low levels of BDNF in pre-frail elderly women suggest that this neurotrophic factor may be a key pathophysiological mediator in the syndrome of frailty. The fact that PTI increased BDNF levels in both groups suggests that it may be possible to modify this phenotype. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study.

PubMed

Gutiérrez, Blanca; Bellón, Juan Á; Rivera, Margarita; Molina, Esther; King, Michael; Marston, Louise; Torres-González, Francisco; Moreno-Küstner, Berta; Moreno-Peral, Patricia; Motrico, Emma; Montón-Franco, Carmen; GildeGómez-Barragán, María J; Sánchez-Celaya, Marta; Díaz-Barreiros, Miguel Á; Vicens, Catalina; de Dios Luna, Juan; Nazareth, Irwin; Cervilla, Jorge

2015-05-01

There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. We explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes.

The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study

PubMed Central

Gutiérrez, Blanca; Bellón, Juan Ángel; Rivera, Margarita; Molina, Esther; King, Michael; Marston, Louise; Torres-González, Francisco; Moreno-Küstner, Berta; Moreno-Peral, Patricia; Motrico, Emma; Montón-Franco, Carmen; GildeGómez-Barragán, María Josefa; Sánchez-Celaya, Marta; Díaz-Barreiros, Miguel Ángel; Vicens, Catalina; de Dios Luna, Juan; Nazareth, Irwin; Cervilla, Jorge

2015-01-01

Background There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. Methods We explored 2- and 3-way gene (SERT and BDNF) × environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. Results Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. Limitations Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. Conclusion Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes. PMID:25510949

Sustained Delivery of Activated Rho GTPases and BDNF Promotes Axon Growth in CSPG-Rich Regions Following Spinal Cord Injury

PubMed Central

Jain, Anjana; McKeon, Robert J.; Brady-Kalnay, Susann M.; Bellamkonda, Ravi V.

2011-01-01

Background Spinal cord injury (SCI) often results in permanent functional loss. This physical trauma leads to secondary events, such as the deposition of inhibitory chondroitin sulfate proteoglycan (CSPG) within astroglial scar tissue at the lesion. Methodology/Principal Findings We examined whether local delivery of constitutively active (CA) Rho GTPases, Cdc42 and Rac1 to the lesion site alleviated CSPG-mediated inhibition of regenerating axons. A dorsal over-hemisection lesion was created in the rat spinal cord and the resulting cavity was conformally filled with an in situ gelling hydrogel combined with lipid microtubes that slowly released constitutively active (CA) Cdc42, Rac1, or Brain-derived neurotrophic factor (BDNF). Treatment with BDNF, CA-Cdc42, or CA-Rac1 reduced the number of GFAP-positive astrocytes, as well as CSPG deposition, at the interface of the implanted hydrogel and host tissue. Neurofilament 160kDa positively stained axons traversed the glial scar extensively, entering the hydrogel-filled cavity in the treatments with BDNF and CA-Rho GTPases. The treated animals had a higher percentage of axons from the corticospinal tract that traversed the CSPG-rich regions located proximal to the lesion site. Conclusion Local delivery of CA-Cdc42, CA-Rac1, and BDNF may have a significant therapeutic role in overcoming CSPG-mediated regenerative failure after SCI. PMID:21283639

Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons

PubMed Central

Sampathkumar, Charanya; Wu, Yuan-Ju; Vadhvani, Mayur; Trimbuch, Thorsten; Eickholt, Britta; Rosenmund, Christian

2016-01-01

Mutations in the MECP2 gene cause the neurodevelopmental disorder Rett syndrome (RTT). Previous studies have shown that altered MeCP2 levels result in aberrant neurite outgrowth and glutamatergic synapse formation. However, causal molecular mechanisms are not well understood since MeCP2 is known to regulate transcription of a wide range of target genes. Here, we describe a key role for a constitutive BDNF feed forward signaling pathway in regulating synaptic response, general growth and differentiation of glutamatergic neurons. Chronic block of TrkB receptors mimics the MeCP2 deficiency in wildtype glutamatergic neurons, while re-expression of BDNF quantitatively rescues MeCP2 deficiency. We show that BDNF acts cell autonomous and autocrine, as wildtype neurons are not capable of rescuing growth deficits in neighboring MeCP2 deficient neurons in vitro and in vivo. These findings are relevant for understanding RTT pathophysiology, wherein wildtype and mutant neurons are intermixed throughout the nervous system. DOI: http://dx.doi.org/10.7554/eLife.19374.001 PMID:27782879

Circulating brain derived neurotrophic factor (BDNF) and frequency of BDNF positive T cells in peripheral blood in human ischemic stroke: Effect on outcome.

PubMed

Chan, Adeline; Yan, Jun; Csurhes, Peter; Greer, Judith; McCombe, Pamela

2015-09-15

The aim of this study was to measure the levels of circulating BDNF and the frequency of BDNF-producing T cells after acute ischaemic stroke. Serum BDNF levels were measured by ELISA. Flow cytometry was used to enumerate peripheral blood leukocytes that were labelled with antibodies against markers of T cells, T regulatory cells (Tregs), and intracellular BDNF. There was a slight increase in serum BDNF levels after stroke. There was no overall difference between stroke patients and controls in the frequency of CD4(+) and CD8(+) BDNF(+) cells, although a subgroup of stroke patients showed high frequencies of these cells. However, there was an increase in the percentage of BDNF(+) Treg cells in the CD4(+) population in stroke patients compared to controls. Patients with high percentages of CD4(+) BDNF(+) Treg cells had a better outcome at 6months than those with lower levels. These groups did not differ in age, gender or initial stroke severity. Enhancement of BDNF production after stroke could be a useful means of improving neuroprotection and recovery after stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1.

PubMed

Majumder, Pritha; Chattopadhyay, Biswanath; Mazumder, Arindam; Das, Pradeep; Bhattacharyya, Nitai P

2006-05-01

To decipher the pathway of apoptosis induction downstream to caspase-8 activation by exogenous expression of Hippi, an interactor of huntingtin-interacting protein Hip1, we studied apoptosis in HeLa and Neuro2A cells expressing GFP-tagged Hippi. Nuclear fragmentation, caspase-1, caspase-8, caspase-9/caspase-6 and caspase-3 activation were increased significantly in Hippi expressing cells. Cleavage of Bid, release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria were also increased in GFP-Hippi expressing cells. It was observed that caspase-1 and caspase-8 activation was earlier than caspase-3 activation and nuclear fragmentation. Expression of caspase-1, caspase-3 and caspase-7 was increased while anti-apoptotic gene Bcl-2 and mitochondrial genes ND1 and ND4 were reduced in Hippi expressing cells. Besides, the expression SDHA and SDHB, nuclear genes, subunits of mitochondrial complex II were decreased in GFP-Hippi expressing cells. Taken together, we concluded that Hippi expression induced apoptosis by releasing AIF and cytochrome c from mitochondria, activation of caspase-1 and caspase-3, and altering the expression of apoptotic genes and genes involved in mitochondrial complex I and II.

Genetic association of single nucleotide polymorphisms of FZD4 and BDNF genes with retinopathy of prematurity.

PubMed

Lasabova, Zora; Stanclova, Andrea; Grendar, Marian; Mikolajcikova, Silvia; Calkovska, Andrea; Lenhartova, Nina; Ziak, Peter; Matasova, Katarina; Caprnda, Martin; Kruzliak, Peter; Zibolen, Mirko

2018-06-01

Retinopathy of prematurity (ROP) is a multifactorial disease occurring in preterm neonates, caused by incorrect development of retinal blood vessels. It has been suggested that, in addition to gestational age, weight, and oxygen supplementation, genetic factors can play a role in the pathogenesis of ROP. In the present prospective study, 97 neonates were enrolled based on the gestational age and weight, and genomic DNA from patients diagnosed with ROP and premature newborns without ROP was collected. The DNA sequence of protein coding and 5´and 3´ untranslated regions (UTRs) of the frizzled-4 (FZD4) gene and the genotype of the locus rs7934165:G˃A (NM_170731.4: c.3 + 10976 C˃T) within the brain-derived neurotrophic factor gene (BDNF) were determined. We detected a significant association between rs61749246:C˃A (NM_012193.3: c.*2G˃T) and ROP in a general genetic model as well as in a multiplicative model and by the Cochran-Armitage test for trend. Moreover, rs61749246 was strongly associated with ROP, requiring surgical intervention. We suggest that rs61749246:C˃A of the FZD4 gene is likely associated with the development of ROP. It is necessary to confirm this suggestion in larger studies.

Performance-related increases in hippocampal N-acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val homozygotes.

PubMed

Lövdén, Martin; Schaefer, Sabine; Noack, Hannes; Kanowski, Martin; Kaufmann, Jörn; Tempelmann, Claus; Bodammer, Nils Christian; Kühn, Simone; Heinze, Hans-Jochen; Lindenberger, Ulman; Düzel, Emrah; Bäckman, Lars

2011-06-01

Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

Innate BDNF expression is associated with ethanol intake in alcohol-preferring AA and alcohol-avoiding ANA rats.

PubMed

Raivio, Noora; Miettinen, Pekka; Kiianmaa, Kalervo

2014-09-04

We have shown recently that acute administration of ethanol modulates the expression of brain-derived neurotrophic factor (BDNF) in several rat brain areas known to be involved in the development of addiction to ethanol and other drugs of abuse, suggesting that BDNF may be a factor contributing to the neuroadaptive changes set in motion by ethanol exposure. The purpose of the present study was to further clarify the role of BDNF in reinforcement from ethanol and in the development of addiction to ethanol by specifying the effect of acute administration of ethanol (1.5 or 3.0 g/kg i.p.) on the expression profile of BDNF mRNA in the ventral tegmental area and in the terminal areas of the mesolimbic dopamine pathway in the brain of alcohol-preferring AA and alcohol-avoiding ANA rats, selected for high and low voluntary ethanol intake, respectively. The level of BDNF mRNA expression was higher in the amygdala and ventral tegmental area of AA than in those of ANA rats, and there was a trend for a higher level in the nucleus accumbens. In the amygdala and hippocampus, a biphasic change in the BDNF mRNA levels was detected: the levels were decreased at 3 and 6h but increased above the basal levels at 24h. Furthermore, there was a difference between the AA and ANA lines in the effect of ethanol, the ANA rats showing an increase in BDNF mRNA levels while such a change was not seen in AA rats. These findings suggest that the innate levels of BDNF expression may play a role in the mediation of the reinforcing effects of ethanol and in the control of ethanol intake. Copyright © 2014 Elsevier B.V. All rights reserved.

Merkel Cell-Driven BDNF Signaling Specifies SAI Neuron Molecular and Electrophysiological Phenotypes.

PubMed

Reed-Geaghan, Erin G; Wright, Margaret C; See, Lauren A; Adelman, Peter C; Lee, Kuan Hsien; Koerber, H Richard; Maricich, Stephen M

2016-04-13

The extent to which the skin instructs peripheral somatosensory neuron maturation is unknown. We studied this question in Merkel cell-neurite complexes, where slowly adapting type I (SAI) neurons innervate skin-derived Merkel cells. Transgenic mice lacking Merkel cells had normal dorsal root ganglion (DRG) neuron numbers, but fewer DRG neurons expressed the SAI markers TrkB, TrkC, and Ret. Merkel cell ablation also decreased downstream TrkB signaling in DRGs, and altered the expression of genes associated with SAI development and function. Skin- and Merkel cell-specific deletion of Bdnf during embryogenesis, but not postnatal Bdnf deletion or Ntf3 deletion, reproduced these results. Furthermore, prototypical SAI electrophysiological signatures were absent from skin regions where Bdnf was deleted in embryonic Merkel cells. We conclude that BDNF produced by Merkel cells during a precise embryonic period guides SAI neuron development, providing the first direct evidence that the skin instructs sensory neuron molecular and functional maturation. Peripheral sensory neurons show incredible phenotypic and functional diversity that is initiated early by cell-autonomous and local environmental factors found within the DRG. However, the contribution of target tissues to subsequent sensory neuron development remains unknown. We show that Merkel cells are required for the molecular and functional maturation of the SAI neurons that innervate them. We also show that this process is controlled by BDNF signaling. These findings provide new insights into the regulation of somatosensory neuron development and reveal a novel way in which Merkel cells participate in mechanosensation. Copyright © 2016 the authors 0270-6474/16/364362-15$15.00/0.

Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling.

PubMed

Lee, Min Chul; Okamoto, Masahiro; Liu, Yu Fan; Inoue, Koshiro; Matsui, Takashi; Nogami, Haruo; Soya, Hideaki

2012-10-15

Although voluntary running has beneficial effects on hippocampal cognitive functions if done abundantly, it is still uncertain whether resistance running would be the same. For this purpose, voluntary resistance wheel running (RWR) with a load is a suitable model, since it allows increased work levels and resultant muscular adaptation in fast-twitch muscle. Here, we examined whether RWR would have potential effects on hippocampal cognitive functions with enhanced hippocampal brain-derived neurotrophic factor (BDNF), as does wheel running without a load (WR). Ten-week-old male Wistar rats were assigned randomly to sedentary (Sed), WR, and RWR (to a maximum load of 30% of body weight) groups for 4 wk. We found that in RWR, work levels increased with load, but running distance decreased by about half, which elicited muscular adaptation for fast-twitch plantaris muscle without causing any negative stress effects. Both RWR and WR led to improved spatial learning and memory as well as gene expressions of hippocampal BDNF signaling-related molecules. RWR increased hippocampal BDNF, tyrosine-related kinase B (TrkB), and cAMP response element-binding (CREB) protein levels, whereas WR increased only BDNF. With both exercise groups, there were correlations between spatial memory and BDNF protein (r = 0.41), p-CREB protein (r = 0.44), and work levels (r = 0.77). These results suggest that RWR plays a beneficial role in hippocampus-related cognitive functions associated with hippocampal BDNF signaling, even with short distances, and that work levels rather than running distance are more determinant of exercise-induced beneficial effects in wheel running with and without a load.

BDNF contributes to the genetic variance of milk fat yield in german holstein cattle.

PubMed

Zielke, Lea G; Bortfeldt, Ralf H; Tetens, Jens; Brockmann, Gudrun A

2011-01-01

The gene encoding the brain-derived neurotrophic factor (BDNF) has been repeatedly associated with human obesity. As such, it could also contribute to the regulation of energy partitioning and the amount of secreted milk fat during lactation, which plays an important role in milk production in dairy cattle. Therefore, we performed an association study using estimated breeding values (EBVs) of bulls and yield deviations of German Holstein dairy cattle to test the effect of BDNF on milk fat yield (FY). A highly significant effect (corrected p-value = 3.362 × 10(-4)) was identified for an SNP 168 kb up-stream of the BDNF transcription start. The association tests provided evidence for an additive allele effect of 5.13 kg of fat per lactation on the EBV for milk FY in bulls and 6.80 kg of fat of the own production performance in cows explaining 1.72 and 0.60% of the phenotypic variance in the analyzed populations, respectively. The analyses of bulls and cows consistently showed three haplotype groups that differed significantly from each other, suggesting at least two different mutations in the BDNF region affecting the milk FY. The FY increasing alleles also had low but significant positive effects on protein and total milk yield which suggests a general role of the BDNF region in energy partitioning, rather than a specific regulation of fat synthesis. The results obtained in dairy cattle suggest similar effects of BDNF on milk composition in other species, including man.

BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF.

PubMed

Lim, Yen Ying; Rainey-Smith, Stephanie; Lim, Yoon; Laws, Simon M; Gupta, Veer; Porter, Tenielle; Bourgeat, Pierrick; Ames, David; Fowler, Christopher; Salvado, Olivier; Villemagne, Victor L; Rowe, Christopher C; Masters, Colin L; Zhou, Xin Fu; Martins, Ralph N; Maruff, Paul

2017-11-01

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ- or Aβ+. At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ- Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.

Serum pro-BDNF/BDNF as a treatment biomarker for response to docosahexaenoic acid in traumatized people vulnerable to developing psychological distress: a randomized controlled trial.

PubMed

Matsuoka, Y; Nishi, D; Tanima, Y; Itakura, M; Kojima, M; Hamazaki, K; Noguchi, H; Hamazaki, T

2015-07-07

Our open-label pilot study showed that supplementation with docosahexaenoic acid (DHA) increased serum brain-derived neurotrophic factor (BDNF) levels and that there might be an association between changes in serum BDNF levels and reduced psychological distress. Animal research has indicated that a DHA-enriched diet increases BDNF in the brain. In this randomized double-blind controlled trial of severely injured patients vulnerable to posttraumatic stress disorder (PTSD) and depression, we examined whether DHA increases serum BDNF levels and whether changes in BDNF levels are associated with subsequent symptoms of PTSD and depression. Patients received 1470 mg per day of DHA plus 147 mg per day of eicosapentaenoic acid (EPA; n = 53) or placebo (n = 57) for 12 weeks. Serum levels of mature BDNF and precursor pro-BDNF at baseline and 12-week follow-up were measured using enzyme-linked immunosorbent assay kits. At 12 weeks, we used the Clinician-Administered PTSD Scale to assess PTSD symptoms and depressive symptoms by the Montgomery-Åsberg Depression Rating Scale. We found a significant increase in serum BDNF levels during the trial in the DHA and placebo groups with no interaction between time and group. Changes in BDNF levels were not associated with PTSD severity but negatively associated with depression severity (Spearman's ρ = -0.257, P = 0.012). Changes in pro-BDNF were also negatively associated with depression severity (Spearman's ρ = -0.253, P = 0.013). We found no specific effects of DHA on increased serum levels of BDNF and pro-BDNF; however, evidence in this study suggests that increased BDNF and pro-BDNF have a protective effect by minimizing depression severity.

Association study between BDNF C-281A polymorphism and paranoid schizophrenia in Polish population.

PubMed

Suchanek, Renata; Owczarek, Aleksander; Kowalski, Jan

2012-01-01

Brain-derived neurotrophic factor (BDNF) is one of the candidate genes for schizophrenia. Polymorphism C-281A (rs28383487) in BDNF gene leads to the reduction of promoter activity in the hippocampal neurons in vitro. To our knowledge, this is the first study to examine the influence of alleles and genotypes of BDNF C-281A polymorphism on development, as well as the clinical course (age of onset, suicidal behaviour and psychopathology) of paranoid schizophrenia. The psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) as subscale scores and also single-item scores. We have also performed the haplotype analysis with val66met BDNF polymorphism, which is known to be involved in the pathogenesis of schizophrenia. We have not found significant differences in the distribution of genotypes and alleles between schizophrenic patients and controls in both the overall analysis, as well as sex stratified. Also, we have not shown statistically significant differences between genotype groups and PANSS scale. However, an association between C-281A polymorphism and time of the first episode of paranoid schizophrenia was revealed. Genotype C/A had been connected with later age of onset of paranoid schizophrenia in men but not in women (p < 0.01). The C-281A and val66met polymorphisms have been in a strong linkage disequilibrium (D' = 0.9875; p < 0.05). The haplotype analysis has shown a tendency to a significantly lower frequency of the Met-C haplotype in the schizophrenia group compared to the controls.

[Influence of chronic alcohol treatment on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes in the mouse brain: Role of the C1473G polymorphism in the gene encoding tryptophan hydroxylase 2].

PubMed

Bazovkina, D V; Tsybko, A S; Filimonova, E A; Ilchibaeva, T V; Naumenko, V S

2016-01-01

Tryptophan hydroxylase 2 (Tph-2) is the key enzyme in serotonin biosynthesis. Serotonin is one of the main neurotransmitters involved in the regulation of various physiological functions and behavior patterns. The influence of chronic ethanol consumption on the expression of the Bdnf, Bax, Bcl-xL, and CASP3 genes was studied in the brain structures of B6-1473C (C/C) and B6-1473G (G/G) mice that had been obtained on the base of the C57BL/6 strain. The strains differed in the genotype for the C1473G single nucleotide polymorphism in the Tph-2 gene and in Tph-2 enzyme activity. It was found that chronic alcohol treatment led to a significant increase in the expression of the Bdnf gene in the midbrain of B6-1473G mice, but not in B6-1473С. Chronic alcohol treatment considerably decreased the expression of the ultimate brain apoptosis effector, caspase 3, in the frontal cortex, but increased it in the hippocampus of B6-1473G mice. At the same time, chronic ethanol administration reduced the level of the antiapoptotic Bcl-xL mRNA in the midbrain of B6-1473C mice. Thus, the C1473G polymorphism in the Tph-2 gene considerably influenced the changes in the expression patterns of genes involved in the regulation of neurogenesis and neural apoptosis induced by chronic ethanol treatment.

The influence of infant-caregiver experiences on amygdala Bdnf, OXTr, and NPY expression in developing and adult male and female rats.

PubMed

Hill, Kathryn T; Warren, Megan; Roth, Tania L

2014-10-01

Previous work with various animal models has demonstrated that alterations in the caregiving environment produce long-term changes in anxiety-related and social behaviors, as well as amygdala gene expression. We previously introduced a rodent model in which the timing and duration of exposure to maltreatment or nurturing care outside the home cage can be controlled to assess neurobiological outcomes. Here we sought to determine whether our brief experimental conditions produce changes in gene expression within the developing and adult amygdala. Using a candidate gene approach, we examined fold mRNA changes for the Brain-derived neurotrophic factor (Bdnf), Oxytocin receptor (OXTr), and Neuropeptide Y (NPY) genes, which are all highly expressed in the amygdala and play important roles in anxiety-related and social behaviors. In adults, significant group differences were detected for only Bdnf, with higher levels of Bdnf mRNA for females that had been exposed to maltreatment and males exposed to nurturing care outside the home cage relative to littermate controls. For pups, significant group differences were detected for only OXTr, with lower levels of OXTr mRNA in females exposed to maltreatment. Finally, for adolescents, maltreated-females showed significant changes in Bdnf (decreased), OXTr (decreased), and NPY (increased) mRNA relative to controls. These data illustrate the ability of brief, but repeated exposure to different caregiving environments during the first postnatal week to have long-term effects on gene expression within the developing and adult amygdala, especially for females. Copyright © 2014 Elsevier B.V. All rights reserved.

Impaired eye-blink conditioning in waggler, a mutant mouse with cerebellar BDNF deficiency.

PubMed

Bao, S; Chen, L; Qiao, X; Knusel, B; Thompson, R F

1998-01-01

In addition to their trophic functions, neurotrophins are also implicated in synaptic modulation and learning and memory. Although gene knockout techniques have been used widely in studying the roles of neurotrophins at molecular and cellular levels, behavioral studies using neurotrophin knockouts are limited by the early-onset lethality and various sensory deficits associated with the gene knockout mice. In the present study, we found that in a spontaneous mutant mouse, waggler, the expression of brain-derived neurotrophic factor (BDNF) was selectively absent in the cerebellar granule cells. The cytoarchitecture of the waggler cerebellum appeared to be normal at the light microscope level. The mutant mice exhibited no sensory deficits to auditory stimuli or heat-induced pain. However, they were massively impaired in classic eye-blink conditioning. These results suggest that BDNF may have a role in normal cerebellar neuronal function, which, in turn, is essential for classic eye-blink conditioning.

BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs.

PubMed

Lipska, B K; Khaing, Z Z; Weickert, C S; Weinberger, D R

2001-07-01

Brain-derived neurotrophic factor (BDNF) plays an important role in development, synapse remodelling and responses to stress and injury. Its abnormal expression has been implicated in schizophrenia, a neuropsychiatric disorder in which abnormal neural development of the hippocampus and prefrontal cortex has been postulated. To clarify the effects of antipsychotic drugs used in the therapy of schizophrenia on BDNF mRNA, we studied its expression in rats treated with clozapine and haloperidol and in rats with neonatal lesions of the ventral hippocampus, used as an animal model of schizophrenia. Both antipsychotic drugs reduced BDNF expression in the hippocampus of control rats, but did not significantly lower its expression in the prefrontal cortex. The neonatal hippocampal lesion itself suppressed BDNF mRNA expression in the dentate gyrus and tended to reduce its expression in the prefrontal cortex. These results indicate that, unlike antidepressants, antipsychotics down-regulate BDNF mRNA, and suggest that their therapeutic properties are not mediated by stimulation of this neurotrophin. To the extent that the lesioned rat models some pathophysiological aspects of schizophrenia, our data suggest that a neurodevelopmental insult might suppress expression of the neurotrophin in certain brain regions.

Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression.

PubMed

Chen, J; Li, X; McGue, M

2012-11-01

There is a strong etiological link between brain-derived neurotrophic factor and depression, but the neurocellular mechanisms and gene-environment interactions remain obscure. This study investigated whether one functional polymorphism in the brain-derived neurotrophic factor gene (BDNF Val66Met) modulates the influence of stressful life events on adolescent depressive symptoms. A total of 780 pairs of ethnic Han Chinese adolescent twins, 11-17 years of age, were randomly assigned to one of two subgroups (twin1 and twin2). All subjects were genotyped as Val/Val, Val/Met or Met/Met, and assessed for depressive symptoms using the Children's Depression Inventory. The level of environmental stress was estimated by the frequency of stressful life events using the Life Events Checklist. The frequency of stressful life events was significantly correlated with depressive symptoms (twin1: β = 0.21, P = 0.01; twin2: β = 0.27, P < 0.01), but there was no significant main effect of the BDNF Val66Met genotype on depressive symptoms. In both subgroups, however, the interaction between the BDNF Val66Met genotype and stressful life event frequency was significant (twin1: β = 0.19, P = 0.01; twin2: β = 0.15, P = 0.04); individuals with one or two Val alleles demonstrated a greater susceptibility to both the detrimental effects of higher stress and the beneficial effects of lower stress compared to the Met/Met genotype. These findings support the 'differential-susceptibility' hypothesis, whereby the BDNF Val allele modulates the influence of environmental stress on depression by enhancing the neuroplastic response to all life events. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Brain-derived neurotrophic factor (BDNF) in the rostral anterior cingulate cortex (rACC) contributes to neuropathic spontaneous pain-related aversion via NR2B receptors.

PubMed

Zhang, Le; Wang, Gongming; Ma, Jinben; Liu, Chengxiao; Liu, Xijiang; Zhan, Yufeng; Zhang, Mengyuan

2016-10-01

The rostral anterior cingulate cortex (rACC) plays an important role in pain affect. Previous investigations have reported that the rACC mediates the negative affective component of inflammatory pain and contributed to the aversive state of nerve injury-induced neuropathic pain. Brain-derived neurotrophic factor (BDNF), an activity-dependent neuromodulator in the adult brain, is believed to play a role in the development and maintenance of inflammatory and neuropathic pain in the spinal cord. However, whether and how BDNF in the rACC regulates pain-related aversion due to peripheral nerve injury is largely unknown. Behaviorally, using conditioned place preference (CPP) training in rats, which is thought to reveal spontaneous pain-related aversion, we found that CPP was acquired following spinal clonidine in rats with partial sciatic nerve transection. Importantly, BDNF was upregulated within the rACC in of rats with nerve injury and enhanced the CPP acquisition, while a local injection of a BDNF-tropomyosin receptor kinase B (TrkB) antagonist into the rACC completely blocked this process. Finally, we demonstrated that the BDNF/TrkB pathway exerted its function by activating the NR2B receptor, which is widely accepted to be a crucial factor contributing to pain affect. In conclusion, our results demonstrate that the BDNF/TrkB-mediated signaling pathway in the rACC is involved in the development of neuropathic spontaneous pain-related aversion and that this process is dependent upon activation of NR2B receptors. These findings suggest that suppression of the BDNF-related signaling pathway in the rACC may provide a novel strategy to overcome pain-related aversion. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic moderation of child maltreatment effects on depression and internalizing symptoms by 5-HTTLPR, BDNF, NET, and CRHR1 genes in African-American children

PubMed Central

Cicchetti, Dante; Rogosch, Fred A.

2014-01-01

Genetic moderation of the effects of child maltreatment on depression and internalizing symptoms was investigated in a sample of low-income maltreated and nonmaltreated African-American children (N = 1,096). Lifetime child maltreatment experiences were independently coded from Child Protective Services records and maternal report. Child depression and internalizing problems were assessed in the context of a summer research camp by self-report (Children’s Depression Inventory, CDI) and adult counselor-report (Teacher Report Form, TRF). DNA was obtained from buccal cell or saliva samples and genotyped for polymorphisms of the following genes: 5-HTTLPR, BDNF, NET, and CRHR1. ANCOVAs with age and gender as covariates were conducted, with maltreatment status and respective polymorphism as main effects and their GxE interactions. Maltreatment consistently was associated with higher CDI and TRF symptoms. Results for child self-report symptoms indicated a GxE interaction for BDNF and maltreatment. Additionally, BDNF and tri-allelic 5-HTTLPR interacted with child maltreatment in a GxGxE interaction. Analyses for counselor-report of child anxiety/depression symptoms on the TRF indicated moderation of child maltreatment effects by tri-allelic 5-HTTLPR. These effects were elaborated based on variation in developmental timing of maltreatment experiences. NET was found to further moderate the GxE interaction of 5-HTTLPR and maltreatment status revealing a GxGxE interaction. This GxGxE was extended by consideration of variation in maltreatment subtype experiences. Finally, GxGxE effects were observed for the co-action of BDNF and the CRHR1 haplotype. The findings illustrate the variable influence of specific genotypes in GxE interactions based on variation in maltreatment experiences and the importance of a multi-genic approach for understanding influences on depression and internalizing symptoms among African-American children. PMID:25422957

Dose-Dependent Lowering of Mutant Huntingtin Using Antisense Oligonucleotides in Huntington Disease Patients.

PubMed

van Roon-Mom, Willeke M C; Roos, Raymund A C; de Bot, Susanne T

2018-04-01

On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data. This news follows the approval of another therapeutic ASO nusinersen (trade name Spinraza) for a neurological disease, spinal muscular atrophy, by the U.S. Food and Drug Administration and European Medicines Agency, in 2016 and 2017, respectively. Combined, this offers hope for the development of the HTTRx therapy for HD patients.

Plasma BDNF levels following weight recovery in anorexia nervosa.

PubMed

Phillips, Kathryn E; Jimerson, David C; Pillai, Anilkumar; Wolfe, Barbara E

2016-10-15

Preclinical studies have implicated brain-derived neurotrophic factor (BDNF) in the regulation of eating behavior and body weight. As reviewed in this report, prior studies of BDNF levels in anorexia nervosa have yielded variable results, perhaps reflecting effects of malnutrition and psychiatric comorbidity. The goal of the current report was to assess plasma BDNF as a biomarker in weight-recovered individuals with a history of anorexia nervosa (ANWR). Study groups included women meeting criteria for ANWR and healthy female controls. Participants were in a normal weight range, free of current major psychiatric disorder, and free of medication. Self-ratings included eating disorder symptoms, depression and anxiety. Plasma BDNF levels were measured by enzyme linked immunoassay. Plasma BDNF levels were not significantly different for ANWR and control groups. Plasma BDNF levels were inversely correlated with anxiety ratings in controls (p<0.02) but not in the ANWR group. This report provides new evidence that circulating BDNF concentrations do not differ in healthy controls and ANWR free of psychiatric comorbidity. Additionally, the data provide new information on the relationship between plasma BDNF and anxiety in these two study groups. Copyright © 2016 Elsevier Inc. All rights reserved.

Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum.

PubMed

Thompson, Andrew B; Stolyarova, Alexandra; Ying, Zhe; Zhuang, Yumei; Gómez-Pinilla, Fernando; Izquierdo, Alicia

2015-12-01

Exposure to drugs of abuse can produce many neurobiological changes which may lead to increased valuation of rewards and decreased sensitivity to their costs. Many of these behavioral alterations are associated with activity of D2-expressing medium spiny neurons in the striatum. Additionally, Bdnf in the striatum has been shown to play a role in flexible reward-seeking behavior. Given that voluntary aerobic exercise can affect the expression of these proteins in healthy subjects, and that exercise has shown promise as an anti-addictive therapy, we set out to quantify changes in D2 and Bdnf expression in methamphetamine-exposed rats given access to running wheels. Sixty-four rats were treated for two weeks with an escalating dose of methamphetamine or saline, then either sacrificed, housed in standard cages, or given free access to a running wheel for 6 weeks prior to sacrifice. Rats treated with methamphetamine ran significantly greater distances than saline-treated rats, suggesting an augmentation in the reinforcement value of voluntary wheel running. Transcription of Drd2 and Bdnf was assessed via RT-qPCR. Protein expression levels of D2 and phosphorylation of the TrkB receptor were measured via western blot. Drd2 and Bdnf mRNA levels were impacted independently by exercise and methamphetamine, but exposure to methamphetamine prior to the initiation of exercise blocked the exercise-induced changes seen in rats treated with saline. Expression levels of both proteins were elevated immediately after methamphetamine, but returned to baseline after six weeks, regardless of exercise status. Copyright © 2015 Elsevier Ltd. All rights reserved.

Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA) involved in neuroplasticity and the risk for alcohol dependence.

PubMed

Forero, Diego A; López-León, Sandra; Shin, Hyoung Doo; Park, Byung Lae; Kim, Dai-Jin

2015-04-01

Alcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes. In the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity. Forty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity. In terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling.

PubMed

Gideons, Erinn S; Lin, Pei-Yi; Mahgoub, Melissa; Kavalali, Ege T; Monteggia, Lisa M

2017-06-16

Lithium is widely used as a treatment for Bipolar Disorder although the molecular mechanisms that underlie its therapeutic effects are under debate. In this study, we show brain-derived neurotrophic factor (BDNF) is required for the antimanic-like effects of lithium but not the antidepressant-like effects in mice. We performed whole cell patch clamp recordings of hippocampal neurons to determine the impact of lithium on synaptic transmission that may underlie the behavioral effects. Lithium produced a significant decrease in α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes due to postsynaptic homeostatic plasticity that was dependent on BDNF and its receptor tropomyosin receptor kinase B (TrkB). The decrease in AMPAR function was due to reduced surface expression of GluA1 subunits through dynamin-dependent endocytosis. Collectively, these findings demonstrate a requirement for BDNF in the antimanic action of lithium and identify enhanced dynamin-dependent endocytosis of AMPARs as a potential mechanism underlying the therapeutic effects of lithium.

A caged Ab reveals an immediate/instructive effect of BDNF during hippocampal synaptic potentiation

PubMed Central

Kossel, Albrecht H.; Cambridge, Sidney B.; Wagner, Uta; Bonhoeffer, Tobias

2001-01-01

Neurotrophins have been shown to be involved in functional strengthening of central nervous system synapses. Although their general importance in this process is undisputed, it remains unresolved whether neurotrophins are truly mediators of synaptic strengthening or merely important cofactors. To address this question, we have devised a method to inactivate endogenous brain-derived neurotrophic factor (BDNF) with high time resolution by “caging” a function-blocking mAb against BDNF with a photosensitive protecting compound. Different assays were used to show that this inactivation of the Ab is reversible by UV light. Synaptic potentiation after τ-burst stimulation in the CA1 region of acute hippocampal slices was significantly less when applying the unmodified Ab compared with the caged Ab. Importantly, photoactivation of the caged Ab during the time of induction of synaptic enhancement led to a marked decrease in potentiation. Our experiments therefore strengthen the view that endogenous BDNF has fast effects during induction of synaptic plasticity. The results additionally show that caged Abs can provide a tool for precise spatiotemporal control over endogenous protein levels. PMID:11724927

Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling

PubMed Central

Gideons, Erinn S; Lin, Pei-Yi; Mahgoub, Melissa; Kavalali, Ege T; Monteggia, Lisa M

2017-01-01

Lithium is widely used as a treatment for Bipolar Disorder although the molecular mechanisms that underlie its therapeutic effects are under debate. In this study, we show brain-derived neurotrophic factor (BDNF) is required for the antimanic-like effects of lithium but not the antidepressant-like effects in mice. We performed whole cell patch clamp recordings of hippocampal neurons to determine the impact of lithium on synaptic transmission that may underlie the behavioral effects. Lithium produced a significant decrease in α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes due to postsynaptic homeostatic plasticity that was dependent on BDNF and its receptor tropomyosin receptor kinase B (TrkB). The decrease in AMPAR function was due to reduced surface expression of GluA1 subunits through dynamin-dependent endocytosis. Collectively, these findings demonstrate a requirement for BDNF in the antimanic action of lithium and identify enhanced dynamin-dependent endocytosis of AMPARs as a potential mechanism underlying the therapeutic effects of lithium. DOI: http://dx.doi.org/10.7554/eLife.25480.001 PMID:28621662

Sex differences in the effect of acute peripheral IL-1β administration on the brain and serum BDNF and VEGF expression in rats.

PubMed

Obuchowicz, Ewa; Nowacka, Marta; Paul-Samojedny, Monika; Bielecka-Wajdman, Anna M; Małecki, Andrzej

2017-02-01

The present study was designed to evaluate, for the first time, the potential sex differences in BDNF and VEGF systems under normal conditions and in response to IL-1β given ip. Peripheral overproduction of this cytokine mediates the pathophysiology of various acute neuroinflammatory states. Until now, the effect of IL-1β on VEGF expression in rat brain structures and its serum level has not been examined. In male and female rats, the BDNF and VEGF mRNA expression, and BDNF level were evaluated in the amygdala, hippocampus, hypothalamus and pituitary gland. The VEGF levels were determined in the pituitary. Serum BDNF and VEGF levels were also measured. The pituitary BDNF mRNA, and BDNF and VEGF levels were higher in females than in male rats whereas in males, the BDNF levels were higher in the other brain structures. The serum BDNF concentration was similar in both groups but VEGF levels were enhanced in females. Following IL-1β (50μg/kg ip.) administration, a higher serum IL-1β level was detected in females than in males. In male rats, IL-1β decreased BDNF mRNA in all the brain structures, except for the pituitary, and VEGF mRNA in the amygdala. In opposite, IL-1β challenge in females increased the pituitary VEGF mRNA and serum BDNF and VEGF levels. These results suggest that in females BDNF and VEGF may play a more important role in the pituitary function. In males, amygdala trophic system seems to be especially sensitive to the enhanced peripheral IL-1β production. Our findings point to the need to consider sex-related differences to be able to draw reliable conclusions about changes in BDNF and VEGF levels during inflammation. Copyright © 2016 Elsevier Ltd. All rights reserved.

The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): Kill two birds with one stone.

PubMed

Motamedi, Shima; Karimi, Isaac; Jafari, Fariba

2017-06-01

The brain-derived neurotrophic factor (BDNF) is involved in metabolic syndrome (MetS) and neurodegenerative diseases (NDD) like Alzheimer's disease, Huntington's disease, Parkinson's disease and depression. If one factor plays an essential role in the pathogenesis of two diseases, it can be concluded that there might be a common root in these two diseases, as well. This review was aimed to highlight the crucial roles of BDNF in the pathogenesis of MetS and NDD and to introduce sole prophylactic or therapeutic applications, BDNF gene therapy and BDFN administration, in controlling MetS and NDD.

The influence of aging on the methylation status of brain-derived neurotrophic factor gene in blood.

PubMed

Ihara, Kazushige; Fuchikami, Manabu; Hashizume, Masahiro; Okada, Satoshi; Kawai, Hisashi; Obuchi, Shuichi; Hirano, Hirohiko; Fujiwara, Yoshinori; Hachisu, Mitsugu; Hongyong, Kim; Morinobu, Shigeru

2018-06-28

Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of psychiatric disorders in adults and elderly individuals, and as a result, the DNA methylation (DNAm) of the BDNF gene in peripheral tissues including blood has been extensively examined to develop a useful biomarker for psychiatric disorders. However, studies to date have not previously investigated the effect of age on DNAm of the BDNF gene in blood. In this context, we measured DNAm of 39 CpG units in the CpG island at the promoter of exon I of the BDNF gene. We analyzed genomic DNA from peripheral blood of 105 health Japanese women 20 to 80 years of age to identify aging-associated change in DNAm of the BDNF gene. In addition, we examined the relationship between total MMSE scores, numbers of stressful life events, and serum BDNF levels on DNAm of the BDNF gene. The DNAm rate at each CpG unit was measured using a MassArray ® system (Agena Bioscience), and serum BDNF levels were measured by ELISA. There was a significant correlation between DNAm and age in 13 CpGs. However, there was no significant correlation between DNAm and total MMSE scores, numbers of life events, or serum BDNF levels. Despite the small number of subjects and the inclusion of only female subjects, our results suggest that DNAm of 13 CpGs of the BDNF gene may be an appropriate biomarker for aging and useful for predicting increased susceptibility to age-related psychiatric disorders. © 2018 John Wiley & Sons, Ltd.

Apoptosis Signal-Regulating Kinase 1 Is Involved in Brain-Derived Neurotrophic Factor (BDNF)-Enhanced Cell Motility and Matrix Metalloproteinase 1 Expression in Human Chondrosarcoma Cells

PubMed Central

Lin, Chih-Yang; Chang, Sunny Li-Yun; Fong, Yi-Chin; Hsu, Chin-Jung; Tang, Chih-Hsin

2013-01-01

Chondrosarcoma is the primary malignancy of bone that is characterized by a potent capacity to invade locally and cause distant metastasis, and is therefore associated with poor prognoses. Chondrosarcoma further shows a predilection for metastasis to the lungs. The brain-derived neurotrophic factor (BDNF) is a small molecule in the neurotrophin family of growth factors that is associated with the disease status and outcome of cancers. However, the effect of BDNF on cell motility in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma cell lines had significantly higher cell motility and BDNF expression compared to normal chondrocytes. We also found that BDNF increased cell motility and expression of matrix metalloproteinase-1 (MMP-1) in human chondrosarcoma cells. BDNF-mediated cell motility and MMP-1 up-regulation were attenuated by Trk inhibitor (K252a), ASK1 inhibitor (thioredoxin), JNK inhibitor (SP600125), and p38 inhibitor (SB203580). Furthermore, BDNF also promoted Sp1 activation. Our results indicate that BDNF enhances the migration and invasion activity of chondrosarcoma cells by increasing MMP-1 expression through a signal transduction pathway that involves the TrkB receptor, ASK1, JNK/p38, and Sp1. BDNF thus represents a promising new target for treating chondrosarcoma metastasis. PMID:23892595

The influence of BDNF on human umbilical cord blood stem/progenitor cells: implications for stem cell-based therapy of neurodegenerative disorders.

PubMed

Paczkowska, Edyta; Łuczkowska, Karolina; Piecyk, Katarzyna; Rogińska, Dorota; Pius-Sadowska, Ewa; Ustianowski, Przemysław; Cecerska, Elżbieta; Dołęgowska, Barbara; Celewicz, Zbigniew; Machaliński, Bogusław

2015-01-01

Umbilical cord blood (UCB)-derived stem/progenitor cells (SPCs) have demonstrated the potential to improve neurologic function in different experimental models. SPCs can survive after transplantation in the neural microenvironment and indu ce neuroprotection, endogenous neurogenesis by secreting a broad repertoire of trophic and immunomodulatory cytokines. In this study, the influence of brain-derived neurotrophic factor (BDNF) pre-treatment was comprehensively evaluated in a UCB-derived lineage-negative (Lin-) SPC population. UCB-derived Lin- cells were evaluated with respect to the expression of (i) neuronal markers using immunofluorescence staining and (ii) specific (TrkB) receptors for BDNF using flow cytometry. Next, after BDNF pre-treatment, Lin- cells were extensively assessed with respect to apoptosis using Western blotting and proliferation via BrdU incorporation. Furthermore, NT-3 expression levels in Lin- cells using RQ PCR and antioxidative enzyme activities were assessed. We demonstrated neuronal markers as well as TrkB expression in Lin- cells and the activation of the TrkB receptor by BDNF. BDNF pre-treatment diminished apoptosis in Lin- cells and influenced the proliferation of these cells. We observed significant changes in antioxidants as well as in the increased expression of NT-3 in Lin- cells following BDNF exposure. Complex global miRNA and mRNA profiling analyses using microarray technology and GSEA revealed the differential regulation of genes involved in the proliferation, gene expression, biosynthetic processes, translation, and protein targeting. Our results support the hypothesis that pre-treatment of stem/progenitor cells could be beneficial and may be used as an auxiliary strategy for improving the properties of SPCs.

Interaction Between 5-HTTLPR and BDNF Val66Met Polymorphisms on HPA Axis Reactivity in Preschoolers

PubMed Central

Dougherty, Lea R.; Klein, Daniel N.; Congdon, Eliza; Canli, Turhan; Hayden, Elizabeth P.

2009-01-01

This study examined whether the interaction between the serotonin transporter promoter region (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms was associated with hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. A community sample of 144 preschool-aged children was genotyped and exposed to stress-inducing laboratory tasks. Salivary cortisol was obtained at four time points during a standardized laboratory assessment before and after stressors involving separation from a parent and frustrating tasks. Children homozygous for the short-5-HTTLPR allele and carrying the Met-BDNF allele evidenced a significantly lower initial level of cortisol, followed by a positive increase in cortisol in response to the laboratory stressors. In contrast, children who were homozygous for the short-5-HTTLPR and the Val-BDNF alleles evidenced a greater decline in cortisol in response to the laboratory stressors. Findings indicated that the BDNF gene moderated the association between 5-HTTLPR and children’s biological stress responses, suggesting that epistatic effects play a role in individual differences in stress regulation, and possibly genetic vulnerability to stress-related disorders. PMID:19914329

Paradoxical visuomotor adaptation to reversed visual input is predicted by BDNF Val66Met polymorphism

PubMed Central

Barton, Brian; Treister, Andrew; Humphrey, Melanie; Abedi, Garen; Cramer, Steven C.; Brewer, Alyssa A.

2014-01-01

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain, influencing neural development, plasticity, and repair (Chen et al., 2004; Thoenen, 1995). The BDNF gene contains a single-nucleotide polymorphism (SNP) called Val66Met. The Met allele interferes with intracellular BDNF-trafficking, decreases activity-dependent BDNF secretion, and consequently is often associated with a shift from plasticity to stability in neural circuits (Egan et al., 2003). We investigated the behavioral consequences of the presence of the Met allele by comparing how 40 heterozygous subjects with the Val/Met genotype and 35 homozygous subjects with the Val/Val genotype performed on visuomotor tasks (reaching and navigation) under two conditions: normal vision and completely left-right reversed vision. As expected, subjects did not differ in their short-term ability to learn the tasks with normal vision (p = 0.58). Intuitively, it would be expected that homozygous Val/Val subjects with a propensity for greater BDNF-induced activity-dependent plasticity would learn new tasks more quickly than heterozygous Val/Met subjects with decreased BDNF secretion (Gilbert, Li, & Piech, 2009). However, we found the opposite here. When short-term mechanisms of visuomotor adaptation were engaged to compensate for the misalignment of visual and somatomotor information created by the left-right reversal of vision, heterozygous Val/Met subjects learned significantly more quickly than their homozygous Val/Val counterparts (p = 0.027). Our results demonstrate the paradoxical finding that the presence of the Met allele, which is thought to promote cortical stability, here improves immediate visuomotor adaptation to left–right-reversed visual input. PMID:25104829

Upregulation of blood proBDNF and its receptors in major depression.

PubMed

Zhou, Li; Xiong, Jing; Lim, Yoon; Ruan, Ye; Huang, Chaohong; Zhu, Yuhong; Zhong, Jin-hua; Xiao, Zhicheng; Zhou, Xin-Fu

2013-09-25

In recent decades, the role of brain-derived neurotrophic factor (BDNF) in depression has received intensive attention. However, the relationship between proBDNF and depression has not been clearly elucidated. Forty drug-free women patients diagnosed with major depression and 50 healthy female controls were enrolled in our study. Peripheral blood was sampled from all the subjects. With the blood samples, we assessed the relationship between BDNF and major depression from following aspects: the levels of BDNF, proBDNF and their receptors in the sera and lymphocytes. The mRNA levels of these factors in lymphocytes were also examined. Furthermore, the correlations between each factor and the severity of major depression were tested. It was found that: (a) the protein and serum levels of proBDNF, sortilin and p75NTR were higher in major depressive patients than in healthy controls while mature BDNF and TrkB levels were lower; (b) the BDNF, TrkB, sortilin and p75NTR mRNA levels changed in line with their protein levels; (c) The levels of mature BDNF and TrkB had negative correlations with the major depression severity, and the levels of proBDNF, p75NTR and sortilin were positively correlated with the scores of HRSD-21; (d) the ratio of proBDNF and mBDNF was imbalanced in major depressive patients. The balance between the proBDNF/p75NTR/sortilin and mBDNF/TrkB signaling pathways appears dysregulated in major depression and both pathways should be considered as biomarkers for the major depression More cases on both genders should be enrolled in our study. And further works on the mechanisms of how BDNF and its receptors are regulated in depression should also be carried out. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

High abundance of BDNF within glutamatergic presynapses of cultured hippocampal neurons

PubMed Central

Andreska, Thomas; Aufmkolk, Sarah; Sauer, Markus; Blum, Robert

2014-01-01

In the mammalian brain, the neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key factor for synaptic refinement, plasticity and learning. Although BDNF-induced signaling cascades are well known, the spatial aspects of the synaptic BDNF localization remained unclear. Recent data provide strong evidence for an exclusive presynaptic location and anterograde secretion of endogenous BDNF at synapses of the hippocampal circuit. In contrast, various studies using BDNF overexpression in cultured hippocampal neurons support the idea that postsynaptic elements and other dendritic structures are the preferential sites of BDNF localization and release. In this study we used rigorously tested anti-BDNF antibodies and achieved a dense labeling of endogenous BDNF close to synapses. Confocal microscopy showed natural BDNF close to many, but not all glutamatergic synapses, while neither GABAergic synapses nor postsynaptic structures carried a typical synaptic BDNF label. To visualize the BDNF distribution within the fine structure of synapses, we implemented super resolution fluorescence imaging by direct stochastic optical reconstruction microscopy (dSTORM). Two-color dSTORM images of neurites were acquired with a spatial resolution of ~20 nm. At this resolution, the synaptic scaffold proteins Bassoon and Homer exhibit hallmarks of mature synapses and form juxtaposed bars, separated by a synaptic cleft. BDNF imaging signals form granule-like clusters with a mean size of ~60 nm and are preferentially found within the fine structure of the glutamatergic presynapse. Individual glutamatergic presynapses carried up to 90% of the synaptic BDNF immunoreactivity, and only a minor fraction of BDNF molecules was found close to the postsynaptic bars. Our data proof that hippocampal neurons are able to enrich and store high amounts of BDNF in small granules within the mature glutamatergic presynapse, at a principle site of synaptic plasticity. PMID:24782711

The BDNF Val66Met Polymorphism Interacts with Maternal Parenting Influencing Adolescent Depressive Symptoms: Evidence of Differential Susceptibility Model.

PubMed

Zhang, Leilei; Li, Zhi; Chen, Jie; Li, Xinying; Zhang, Jianxin; Belsky, Jay

2016-03-01

Although depressive symptoms are common during adolescence, little research has examined gene-environment interaction on youth depression. This study chose the brain-derived neurotrophic factor (BDNF) gene, tested the interaction between a functional polymorphism resulting amino acid substitution of valine (Val) to methionine (Met) in the proBDNF protein at codon 66 (Val66Met), and maternal parenting on youth depressive symptoms in a sample of 780 community adolescents of Chinese Han ethnicity (aged 11-17, M = 13.6, 51.3 % females). Participants reported their depressive symptoms and perceived maternal parenting. Results indicated the BDNF Val66Met polymorphism significantly moderated the influence of maternal warmth-reasoning, but not harshness-hostility, on youth depressive symptoms. Confirmatory model evaluation indicated that the interaction effect involving warmth-reasoning conformed to the differential-susceptibility rather than diathesis-stress model of person-X-environment interaction. Thus, Val carriers experienced less depressive symptoms than Met homozygotes when mothering was more positive but more symptoms when mothering was less positive. The findings provided evidence in support of the differential susceptibility hypothesis of youth depressive symptoms and shed light on the importance of examining the gene-environment interaction from a developmental perspective.

Altered declarative memory in introverted middle-aged adults carrying the BDNF val66met allele.

PubMed

De Beaumont, Louis; Fiocco, Alexandra J; Quesnel, Geneviève; Lupien, Sonia; Poirier, Judes

2013-09-15

The val66met polymorphism of the brain-derived neurotrophic factor gene (BDNFMet) is associated with impaired learning/memory function, affective dysregulation and maladaptive personality traits. Here, we examine the potential relationship between the BDNFMet allele, introversion and declarative memory in middle-age adults. A total of 132 middle-aged healthy adults took part in this study that included taking a blood sample for genetic profiling, a short battery of neuropsychological tests and the NEO-Five Factor Inventory (NEO-FFI), widely used to assess the Big Five personality. Controlling for age, level of education and sex, a multiple analysis of covariance (MANCOVA) computing the effect of BDNF polymorphism on extraversion and declarative memory revealed a significant association (D1,128=4.79; p=0.03; ηp(2)=0.053). Using the Sobel Goodman Mediation Test, it was found that 25.61% of the relationship between genotype and declarative memory performance was mediated by introversion. Subsequent correlational analyses yielded a strong and significant correlation (β=0.53; p<0.001) between introversion and declarative memory specific to BDNFMet individuals. this study highlights the pertinence of further investigating gene×personality×environment interactions to account for the significant variability that is observed in cognitive function in late life. Copyright © 2013 Elsevier B.V. All rights reserved.

Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure.

PubMed

Manning, Elizabeth E; van den Buuse, Maarten

2016-05-15

Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

The BDNF Val66Met polymorphism affects HPA-axis reactivity to acute stress.

PubMed

Alexander, Nina; Osinsky, Roman; Schmitz, Anja; Mueller, Eva; Kuepper, Yvonne; Hennig, Juergen

2010-07-01

Growing evidence suggests that individual differences in HPA-axis reactivity to psychosocial stress are partly due to heritable influences. However, knowledge about the role of specific genetic variants remains very limited to date. Since brain-derived neurotrophic factor (BDNF) not only exhibits neurotrophic actions but is also involved in the regulation of hypothalamic neuropeptides, we investigated the role of a common functional polymorphism within the BDNF gene (BDNF Val66Met) in the context of endocrine and cardiovascular stress reactivity. Healthy male adults (N=100) were genotyped and exposed to a standardized laboratory stress task (Public Speaking). Saliva cortisol and self-reported mood levels were obtained at 6 time points prior to the stressor and during an extended recovery period. Furthermore, heart rate reactivity as an indicator of sympathetic activation was monitored continuously during the experimental procedure. We report a small, but significant effect of the BDNF Val66Met polymorphism on stress reactivity. More precisely, carriers of the met-allele showed a significantly attenuated HPA-axis and cardiovascular reactivity to the psychosocial stressor compared to subjects with the val/val genotype. Furthermore, the diminished physiological response in met-allele carriers was also attended by significantly lower self-reported ratings of perceived stress and nervousness. Our findings of a diminished endocrine and cardiovascular stress response in healthy male adults is consistent with a previously published study and adds further evidence for a crucial role of the BDNF Val66Met polymorphism in the modulation of stress reactivity. Copyright 2010. Published by Elsevier Ltd.

H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus

PubMed Central

Prieto, G. Aleph; Petrosyan, Arpine; Loertscher, Brad M.; Dieskau, André P.; Overman, Larry E.; Cotman, Carl W.

2016-01-01

An increasing number of studies show that an altered epigenetic landscape may cause impairments in regulation of learning and memory-related genes within the aged hippocampus, eventually resulting in cognitive deficits in the aged brain. One such epigenetic repressive mark is trimethylation of H3K9 (H3K9me3), which is typically implicated in gene silencing. Here, we identify, for the first time, an essential role for H3K9me3 and its histone methyl transferase (SUV39H1) in mediating hippocampal memory functions. Pharmacological inhibition of SUV39H1 using a novel and selective inhibitor decreased levels of H3K9me3 in the hippocampus of aged mice, and improved performance in the objection location memory and fear conditioning tasks and in a complex spatial environment learning task. The inhibition of SUV39H1 induced an increase in spine density of thin and stubby but not mushroom spines in the hippocampus of aged animals and increased surface GluR1 levels in hippocampal synaptosomes, a key index of spine plasticity. Furthermore, there were changes at BDNF exon I gene promoter, in concert with overall BDNF levels in the hippocampus of drug-treated animals compared with control animals. Together, these data demonstrate that SUV39H1 inhibition and the concomitant H3K9me3 downregulation mediate gene transcription in the hippocampus and reverse age-dependent deficits in hippocampal memory. SIGNIFICANCE STATEMENT Cognitive decline is a debilitating condition associated with not only neurodegenerative diseases but also aging in general. However, effective treatments have been slow to emerge so far. In this study, we demonstrate that epigenetic regulation of key synaptic proteins may be an underlying, yet reversible, cause of this decline. Our findings suggest that histone 3 trimethylation is a probable target for pharmacological intervention that can counteract cognitive decline in the aging brain. Finally, we provide support to the hypothesis that, by manipulating the

BDNF Val66Met but not transcranial direct current stimulation affects motor learning after stroke.

PubMed

van der Vliet, Rick; Ribbers, Gerard M; Vandermeeren, Yves; Frens, Maarten A; Selles, Ruud W

tDCS is a non-invasive neuromodulation technique that has been reported to improve motor skill learning after stroke. However, the contribution of tDCS to motor skill learning has only been investigated in a small number of studies. In addition, it is unclear if tDCS effects are mediated by activity-dependent BDNF release and dependent on timing of tDCS relative to training. Investigate the role of activity-dependent BDNF release and timing of tDCS relative to training in motor skill learning. Double-blind, between-subjects randomized controlled trial of circuit tracing task improvement (ΔMotor skill) in 80 chronic stroke patients who underwent tDCS and were genotyped for BDNF Val66Met. Patients received either short-lasting tDCS (20 min) during training (short-lasting online group), long-lasting tDCS (10 min-25 min break - 10 min) one day before training (long-lasting offline group), short-lasting tDCS one day before training (short-lasting offline group), or sham tDCS. ΔMotor skill was defined as the skill difference on the circuit tracing task between day one and day nine of the study. Having at least one BDNF Met allele was found to diminish ΔMotor skill (β BDNF,Met  = -0.217 95%HDI = [-0.431 -0.0116]), indicating activity-dependent BDNF release is important for motor skill learning after stroke. However, none of the tDCS protocols affected ΔMotor skill (β Short-lasting,online  = 0.0908 95%HDI = [-0.227 0.403]; β Long-lasting,offline  = 0.0242 95%HDI = [-0.292 0.349]; β Short-lasting,offline  = -0.108 95%HDI = [-0.433 0.210]). BDNF Val66Met is a determinant of motor skill learning after stroke and could be important for prognostic models. tDCS does not modulate motor skill learning in our study and might be less effective than previously assumed. Copyright © 2017 Elsevier Inc. All rights reserved.

BDNF and the maturation of posttranscriptional regulatory networks in human SH-SY5Y neuroblast differentiation.

PubMed

Goldie, Belinda J; Barnett, Michelle M; Cairns, Murray J

2014-01-01

The SH-SY5Y culture system is a convenient neuronal model with the potential to elaborate human/primate-specific transcription networks and pathways related to human cognitive disorders. While this system allows for the exploration of specialized features in the human genome, there is still significant debate about how this model should be implemented, and its appropriateness for answering complex functional questions related to human neural architecture. In view of these questions we sought to characterize the posttranscriptional regulatory structure of the two-stage ATRA differentiation, BDNF maturation protocol proposed by Encinas et al. (2000) using integrative whole-genome gene and microRNA (miRNA) expression analysis. We report that ATRA-BDNF induced significant increases in expression of key synaptic genes, brain-specific miRNA and miRNA biogenesis machinery, and in AChE activity, compared with ATRA alone. Functional annotation clustering associated BDNF more significantly with neuronal terms, and with synaptic terms not found in ATRA-only clusters. While our results support use of SH-SY5Y as a neuronal model, we advocate considered selection of the differentiation agent/s relative to the system being modeled.

Non-cell autonomous cell death caused by transmission of Huntingtin aggregates in Drosophila.

PubMed

Babcock, Daniel T; Ganetzky, Barry

2015-01-01

Recent evidence indicates that protein aggregates can spread between neurons in several neurodegenerative diseases but much remains unknown regarding the underlying mechanisms responsible for this spreading and its role in disease progression. We recently demonstrated that mutant Huntingtin aggregates spread between cells within the Drosophila brain resulting in non-cell autonomous loss of a pair of large neurons in the posterior protocerebrum. However, the full extent of neuronal loss throughout the brain was not determined. Here we examine the effects of driving expression of mutant Huntingtin in Olfactory Receptor Neurons (ORNs) by using a marker for cleaved caspase activity to monitor neuronal apoptosis as a function of age. We find widespread caspase activity in various brain regions over time, demonstrating that non-cell autonomous damage is widespread. Improved understanding of which neurons are most vulnerable and why should be useful in developing treatment strategies for neurodegenerative diseases that involve transcellular spreading of aggregates.

Frequency of nuclear mutant huntingtin inclusion formation in neurons and glia is cell-type-specific.

PubMed

Jansen, Anne H P; van Hal, Maurik; Op den Kelder, Ilse C; Meier, Romy T; de Ruiter, Anna-Aster; Schut, Menno H; Smith, Donna L; Grit, Corien; Brouwer, Nieske; Kamphuis, Willem; Boddeke, H W G M; den Dunnen, Wilfred F A; van Roon, Willeke M C; Bates, Gillian P; Hol, Elly M; Reits, Eric A

2017-01-01

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that is caused by a CAG expansion in the Huntingtin (HTT) gene, leading to HTT inclusion formation in the brain. The mutant huntingtin protein (mHTT) is ubiquitously expressed and therefore nuclear inclusions could be present in all brain cells. The effects of nuclear inclusion formation have been mainly studied in neurons, while the effect on glia has been comparatively disregarded. Astrocytes, microglia, and oligodendrocytes are glial cells that are essential for normal brain function and are implicated in several neurological diseases. Here we examined the number of nuclear mHTT inclusions in both neurons and various types of glia in the two brain areas that are the most affected in HD, frontal cortex, and striatum. We compared nuclear mHTT inclusion body formation in three HD mouse models that express either full-length HTT or an N-terminal exon1 fragment of mHTT, and we observed nuclear inclusions in neurons, astrocytes, oligodendrocytes, and microglia. When studying the frequency of cells with nuclear inclusions in mice, we found that half of the population of neurons contained nuclear inclusions at the disease end stage, whereas the proportion of GFAP-positive astrocytes and oligodendrocytes having a nuclear inclusion was much lower, while microglia hardly showed any nuclear inclusions. Nuclear inclusions were also present in neurons and all studied glial cell types in human patient material. This is the first report to compare nuclear mHTT inclusions in glia and neurons in different HD mouse models and HD patient brains. GLIA 2016;65:50-61. © 2016 The Authors. Glia Published by Wiley Periodicals, Inc.

Interaction between job stress and the BDNF Val66Met polymorphism affects depressive symptoms in Chinese healthcare workers.

PubMed

He, Shu-Chang; Wu, Shuang; Wang, Chao; Du, Xiang-Dong; Yin, Guangzhong; Jia, Qiufang; Zhang, Yingyang; Wang, Li; Soares, Jair C; Zhang, Xiang Yang

2018-08-15

Chronic exposure to job-related stress can lead to depression and BDNF polymorphism may play an important role in this process. The role of the stress × BDNF Val66Met interaction in depression has been studied widely using childhood stress, but few studies have utilized chronic stress in adulthood as a moderator. This study was to examine the chronic stress × BDNF Val66Met interaction in job-related depression in the healthcare workers in a Chinese Han population, which has not been reported yet. Using a cross-sectional design, 243 doctors and nurses were recruited from a general hospital in Beijing, and were assessed for depression with Self-rating Depression Scale (SDS), and the stress using the House and Rizzo's Work Stress Scale. The BDNF Val66Met polymorphism was genotyped. There was a significant positive association between job stress and depressive scores (p < 0.001). No significant main effect of the BDNF Val66Met genotype on depressive symptoms was observed (p > 0.05). A statistically significant interaction between BDNF Val66Met and job stress on depressive symptoms was found (p < 0.05); individuals with Val/Val genotype showed a higher SDS score than Met allele carriers only in the low-stress group, without significant differences in SDS score between the BDNF Val66Met subgroups in medium- or high-stress group. Limitations include cross-sectional study design, the small sample size only in healthcare workers and only one polymorphism in BDNF gene was analyzed. Our results suggest a close relationship between job-related stress and depression, and the interaction of the BDNF Val66Met polymorphism and chronic stress in adulthood may impact the depressive symptoms. Copyright © 2018. Published by Elsevier B.V.

The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children

PubMed Central

Jasińska, Kaja K.; Molfese, Peter J.; Kornilov, Sergey A.; Mencl, W. Einar; Frost, Stephen J.; Lee, Maria; Pugh, Kenneth R.; Grigorenko, Elena L.; Landi, Nicole

2016-01-01

Understanding how genes impact the brain’s functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children’s (age 6–10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading–related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes. PMID:27551971

The BDNF Val66Met Polymorphism Influences Reading Ability and Patterns of Neural Activation in Children.

PubMed

Jasińska, Kaja K; Molfese, Peter J; Kornilov, Sergey A; Mencl, W Einar; Frost, Stephen J; Lee, Maria; Pugh, Kenneth R; Grigorenko, Elena L; Landi, Nicole

2016-01-01

Understanding how genes impact the brain's functional activation for learning and cognition during development remains limited. We asked whether a common genetic variant in the BDNF gene (the Val66Met polymorphism) modulates neural activation in the young brain during a critical period for the emergence and maturation of the neural circuitry for reading. In animal models, the bdnf variation has been shown to be associated with the structure and function of the developing brain and in humans it has been associated with multiple aspects of cognition, particularly memory, which are relevant for the development of skilled reading. Yet, little is known about the impact of the Val66Met polymorphism on functional brain activation in development, either in animal models or in humans. Here, we examined whether the BDNF Val66Met polymorphism (dbSNP rs6265) is associated with children's (age 6-10) neural activation patterns during a reading task (n = 81) using functional magnetic resonance imaging (fMRI), genotyping, and standardized behavioral assessments of cognitive and reading development. Children homozygous for the Val allele at the SNP rs6265 of the BDNF gene outperformed Met allele carriers on reading comprehension and phonological memory, tasks that have a strong memory component. Consistent with these behavioral findings, Met allele carriers showed greater activation in reading-related brain regions including the fusiform gyrus, the left inferior frontal gyrus and left superior temporal gyrus as well as greater activation in the hippocampus during a word and pseudoword reading task. Increased engagement of memory and spoken language regions for Met allele carriers relative to Val/Val homozygotes during reading suggests that Met carriers have to exert greater effort required to retrieve phonological codes.

Ultrasound enhances retrovirus-mediated gene transfer.

PubMed

Naka, Toshio; Sakoda, Tsuyoshi; Doi, Takashi; Tsujino, Takeshi; Masuyama, Tohru; Kawashima, Seinosuke; Iwasaki, Tadaaki; Ohyanagi, Mitsumasa

2007-01-01

Viral vector systems are efficient for transfection of foreign genes into many tissues. Especially, retrovirus based vectors integrate the transgene into the genome of the target cells, which can sustain long term expression. However, it has been demonstrated that the transduction efficiency using retrovirus is relatively lower than those of other viruses. Ultrasound was recently reported to increase gene expression using plasmid DNA, with or without, a delivery vehicle. However, there are no reports, which show an ultrasound effect to retrovirus-mediated gene transfer efficiency. Retrovirus-mediated gene transfer systems were used for transfection of 293T cells, bovine aortic endothelial cells (BAECs), rat aortic smooth muscle cells (RASMCs), and rat skeletal muscle myoblasts (L6 cells) with beta-galactosidase (beta-Gal) genes. Transduction efficiency and cell viability assay were performed on 293T cells that were exposed to varying durations (5 to 30 seconds) and power levels (1.0 watts/cm(2) to 4.0 watts/cm(2)) of ultrasound after being transduced by a retrovirus. Effects of ultrasound to the retrovirus itself was evaluated by transduction efficiency of 293T cells. After exposure to varying power levels of ultrasound to a retrovirus for 5 seconds, 293T cells were transduced by a retrovirus, and transduction efficiency was evaluated. Below 1.0 watts/cm(2) and 5 seconds exposure, ultrasound showed increased transduction efficiency and no cytotoxicity to 293T cells transduced by a retrovirus. Also, ultrasound showed no toxicity to the virus itself at the same condition. Exposure of 5 seconds at the power of 1.0 watts/cm(2) of an ultrasound resulted in significant increases in retrovirus-mediated gene expression in all four cell types tested in this experiment. Transduction efficiencies by ultrasound were enhanced 6.6-fold, 4.8-fold, 2.3-fold, and 3.2-fold in 293T cells, BAECs, RASMCs, and L6 cells, respectively. Furthermore, beta-Gal activities were also increased

Huntingtin Interacting Protein 1 mutations lead to abnormal hematopoiesis, spinal defects and cataracts.

PubMed

Oravecz-Wilson, Katherine I; Kiel, Mark J; Li, Lina; Rao, Dinesh S; Saint-Dic, Djenann; Kumar, Priti D; Provot, Melissa M; Hankenson, Kurt D; Reddy, Venkat N; Lieberman, Andrew P; Morrison, Sean J; Ross, Theodora S

2004-04-15

Huntingtin Interacting Protein 1 (HIP1) binds clathrin and AP2, is overexpressed in multiple human tumors, and transforms fibroblasts. The function of HIP1 is unknown although it is thought to play a fundamental role in clathrin trafficking. Gene-targeted Hip1-/- mice develop premature testicular degeneration and severe spinal deformities. Yet, although HIP1 is expressed in many tissues including the spleen and bone marrow and was part of a leukemogenic translocation, its role in hematopoiesis has not been examined. In this study we report that three different mutations of murine Hip1 lead to hematopoietic abnormalities reflected by diminished early progenitor frequencies and resistance to 5-FU-induced bone marrow toxicity. Two of the Hip1 mutant lines also display the previously described spinal defects. These observations indicate that, in addition to being required for the survival/proliferation of cancer cells and germline progenitors, HIP1 is also required for the survival/proliferation of diverse types of somatic cells, including hematopoietic progenitors.

Transdifferentiation of brain-derived neurotrophic factor (BDNF)-secreting mesenchymal stem cells significantly enhance BDNF secretion and Schwann cell marker proteins.

PubMed

Bierlein De la Rosa, Metzere; Sharma, Anup D; Mallapragada, Surya K; Sakaguchi, Donald S

2017-11-01

The use of genetically modified mesenchymal stem cells (MSCs) is a rapidly growing area of research targeting delivery of therapeutic factors for neuro-repair. Cells can be programmed to hypersecrete various growth/trophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) to promote regenerative neurite outgrowth. In addition to genetic modifications, MSCs can be subjected to transdifferentiation protocols to generate neural cell types to physically and biologically support nerve regeneration. In this study, we have taken a novel approach by combining these two unique strategies and evaluated the impact of transdifferentiating genetically modified MSCs into a Schwann cell-like phenotype. After 8 days in transdifferentiation media, approximately 30-50% of transdifferentiated BDNF-secreting cells immunolabeled for Schwann cell markers such as S100β, S100, and p75 NTR . An enhancement was observed 20 days after inducing transdifferentiation with minimal decreases in expression levels. BDNF production was quantified by ELISA, and its biological activity tested via the PC12-TrkB cell assay. Importantly, the bioactivity of secreted BDNF was verified by the increased neurite outgrowth of PC12-TrkB cells. These findings demonstrate that not only is BDNF actively secreted by the transdifferentiated BDNF-MSCs, but also that it has the capacity to promote neurite sprouting and regeneration. Given the fact that BDNF production remained stable for over 20 days, we believe that these cells have the capacity to produce sustainable, effective, BDNF concentrations over prolonged time periods and should be tested within an in vivo system for future experiments. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

The function of BDNF in the adult auditory system.

PubMed

Singer, Wibke; Panford-Walsh, Rama; Knipper, Marlies

2014-01-01

The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Peony glycosides reverse the effects of corticosterone on behavior and brain BDNF expression in rats.

PubMed

Mao, Qing-Qiu; Huang, Zhen; Ip, Siu-Po; Xian, Yan-Fang; Che, Chun-Tao

2012-02-01

Repeated injections of corticosterone (CORT) induce the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in depressive-like behavior. This study aimed to examine the antidepressant-like effect and the possible mechanisms of total glycosides of peony (TGP) in the CORT-induced depression model in rats. The results showed that the 3-week CORT injections induced the significant increase in serum CORT levels in rats. Repeated CORT injections also caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. Moreover, it was found that brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus and frontal cortex were significantly decreased in CORT-treated rats. Treatment of the rats with TGP significantly suppressed the depression-like behavior and increased brain BDNF levels in CORT-treated rats. The results suggest that TGP produces an antidepressant-like effect in CORT-treated rats, which is possibly mediated by increasing BDNF expression in the hippocampus and frontal cortex. Copyright © 2011 Elsevier B.V. All rights reserved.

Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells.

PubMed

Murmann, Andrea E; Gao, Quan Q; Putzbach, William E; Patel, Monal; Bartom, Elizabeth T; Law, Calvin Y; Bridgeman, Bryan; Chen, Siquan; McMahon, Kaylin M; Thaxton, C Shad; Peter, Marcus E

2018-03-01

Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents. © 2018 The Authors.

Blockade of the spinal BDNF-activated JNK pathway prevents the development of antiretroviral-induced neuropathic pain.

PubMed

Sanna, Maria Domenica; Ghelardini, Carla; Galeotti, Nicoletta

2016-06-01

Although antiretroviral agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. The antiretroviral toxic neuropathy induces debilitating and extremely difficult to treat pain syndromes that often lead to discontinuation of antiretroviral therapy. Due to the critical need for the identification of novel therapeutic targets to improve antiretroviral neuropathic pain management, we investigated the role of the JNK signalling pathway in the mechanism of antiretroviral painful neuropathy. Mice were exposed to zalcitabine (2',3'-dideoxycytidine, ddC) and stavudine (2',3'-didehydro-3'-deoxythymidine, d4T) that induced a persistent mechanical allodynia and a transient cold allodynia. Treatment with the JNK blocker SP600125 before antiretroviral administration abolished mechanical hypersensitivity with no effect on thermal response. A robust spinal JNK overphosphorylation was observed on post-injection day 1 and 3, along with a JNK-dependent increase in p-c-Jun and ATF3 protein levels. Co-immunoprecipitation experiments showed the presence of a heterodimeric complex between ATF3 and c-Jun indicating that these transcription factors can act together to regulate transcription through heterodimerization. A rise in BDNF and caspase-3 protein levels was detected on day 1 and BDNF sequestration prevented both caspase-3 and p-JNK increase. These data suggest that BDNF plays a role in the early stages of ddC-induced allodynia by promoting apoptotic events and the activation of a hypernociceptive JNK-mediated pathway. We illustrated the activation of a BDNF-mediated JNK pathway involved in the early events responsible for the promotion of neuropathic pain, leading to a better knowledge of the mechanisms involved in the antiretroviral neuropathy. JNK blockade prevents antiretroviral-induced pain hypersensitivity. This may represent a potential prophylactic treatment of neuropathic pain to improve antiretroviral

Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

PubMed

Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

2013-07-01

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.

The Role of BDNF in the Development of Fear Learning.

PubMed

Dincheva, Iva; Lynch, Niccola B; Lee, Francis S

2016-10-01

Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders. © 2016 Wiley Periodicals, Inc.

The Effect of Exercise Training on Resting Concentrations of Peripheral Brain-Derived Neurotrophic Factor (BDNF): A Meta-Analysis

PubMed Central

Dinoff, Adam; Herrmann, Nathan; Swardfager, Walter; Liu, Celina S.; Sherman, Chelsea; Chan, Sarah; Lanctôt, Krista L.

2016-01-01

Background The mechanisms through which physical activity supports healthy brain function remain to be elucidated. One hypothesis suggests that increased brain-derived neurotrophic factor (BDNF) mediates some cognitive and mood benefits. This meta-analysis sought to determine the effect of exercise training on resting concentrations of BDNF in peripheral blood. Methods MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after exercise interventions ≥ 2 weeks. Risk of bias was assessed using standardized criteria. Standardized mean differences (SMDs) were generated from random effects models. Risk of publication bias was assessed using funnel plots and Egger’s test. Potential sources of heterogeneity were explored in subgroup analyses. Results In 29 studies that met inclusion criteria, resting concentrations of peripheral blood BDNF were higher after intervention (SMD = 0.39, 95% CI: 0.17–0.60, p < 0.001). Subgroup analyses suggested a significant effect in aerobic (SMD = 0.66, 95% CI: 0.33–0.99, p < 0.001) but not resistance training (SMD = 0.07, 95% CI: -0.15–0.30, p = 0.52) interventions. No significant difference in effect was observed between males and females, nor in serum vs plasma. Conclusion Aerobic but not resistance training interventions increased resting BDNF concentrations in peripheral blood. PMID:27658238

Engineered BDNF producing cells as a potential treatment for neurologic disease

PubMed Central

Deng, Peter; Anderson, Johnathon D.; Yu, Abigail S.; Annett, Geralyn; Fink, Kyle D.; Nolta, Jan A.

2018-01-01

Introduction Brain-derived neurotrophic factor (BDNF) has been implicated in wide range of neurological diseases and injury. This neurotrophic factor is vital for neuronal health, survival, and synaptic connectivity. Many therapies focus on the restoration or enhancement of BDNF following injury or disease progression. Areas covered The present review will focus on the mechanisms in which BDNF exerts its beneficial functioning, current BDNF therapies, issues and potential solutions for delivery of neurotrophic factors to the central nervous system, and other disease indications that may benefit from overexpression or restoration of BDNF. Expert opinion Due to the role of BDNF in neuronal development, maturation, and health, BDNF is implicated in numerous neurological diseases making it a prime therapeutic agent. Numerous studies have shown the therapeutic potential of BDNF in a number of neurodegenerative disease models and in acute CNS injury, however clinical translation has fallen short due to issues in delivering this molecule. The use of MSC as a delivery platform for BDNF holds great promise for clinical advancement of neurotrophic factor restoration. The ease with which MSC can be engineered opens the door to the possibility of using this cell-based delivery system to advance a BDNF therapy to the clinic. PMID:27159050

Male-Mediated Gene Flow in Patrilocal Primates

PubMed Central

Schubert, Grit; Stoneking, Colin J.; Arandjelovic, Mimi; Boesch, Christophe; Eckhardt, Nadin; Hohmann, Gottfried; Langergraber, Kevin; Lukas, Dieter; Vigilant, Linda

2011-01-01

Background Many group–living species display strong sex biases in dispersal tendencies. However, gene flow mediated by apparently philopatric sex may still occur and potentially alters population structure. In our closest living evolutionary relatives, dispersal of adult males seems to be precluded by high levels of territoriality between males of different groups in chimpanzees, and has only been observed once in bonobos. Still, male–mediated gene flow might occur through rare events such as extra–group matings leading to extra–group paternity (EGP) and female secondary dispersal with offspring, but the extent of this gene flow has not yet been assessed. Methodology/Principal Findings Using autosomal microsatellite genotyping of samples from multiple groups of wild western chimpanzees (Pan troglodytes verus) and bonobos (Pan paniscus), we found low genetic differentiation among groups for both males and females. Characterization of Y–chromosome microsatellites revealed levels of genetic differentiation between groups in bonobos almost as high as those reported previously in eastern chimpanzees, but lower levels of differentiation in western chimpanzees. By using simulations to evaluate the patterns of Y–chromosomal variation expected under realistic assumptions of group size, mutation rate and reproductive skew, we demonstrate that the observed presence of multiple and highly divergent Y–haplotypes within western chimpanzee and bonobo groups is best explained by successful male–mediated gene flow. Conclusions/Significance The similarity of inferred rates of male–mediated gene flow and published rates of EGP in western chimpanzees suggests this is the most likely mechanism of male–mediated gene flow in this subspecies. In bonobos more data are needed to refine the estimated rate of gene flow. Our findings suggest that dispersal patterns in these closely related species, and particularly for the chimpanzee subspecies, are more variable than

1Interaction between serum BDNF and aerobic fitness predicts recognition memory in healthy young adults

PubMed Central

Whiteman, Andrew; Young, Daniel E.; He, Xuemei; Chen, Tai C.; Wagenaar, Robert C.; Stern, Chantal; Schon, Karin

2013-01-01

Convergent evidence from human and non-human animal studies suggests aerobic exercise and increased aerobic capacity may be beneficial for brain health and cognition. It is thought growth factors may mediate this putative relationship, particularly by augmenting plasticity mechanisms in the hippocampus, a brain region critical for learning and memory. Among these factors, glucocorticoids, brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF), hormones that have considerable and diverse physiological importance, are thought to effect normal and exercise-induced hippocampal plasticity. Despite these predictions, relatively few published human studies have tested hypotheses that relate exercise and fitness to the hippocampus, and none have considered the potential links to all of these hormonal components. Here we present cross-sectional data from a study of recognition memory; serum BDNF, cortisol, IGF-1, and VEGF levels; and aerobic capacity in healthy young adults. We measured circulating levels of these hormones together with performance on a recognition memory task, and a standard graded treadmill test of aerobic fitness. Regression analyses demonstrated BDNF and aerobic fitness predict recognition memory in an interactive manner. In addition, IGF-1 was positively associated with aerobic fitness, but not with recognition memory. Our results may suggest an exercise adaptation-related change in the BDNF dose-response curve that relates to hippocampal memory. PMID:24269495

BDNF Met66 modulates the cumulative effect of psychosocial childhood adversities on major depression in adolescents.

PubMed

Cruz-Fuentes, Carlos S; Benjet, Corina; Martínez-Levy, Gabriela A; Pérez-Molina, Amado; Briones-Velasco, Magdalena; Suárez-González, Jesús

2014-03-01

The interplay among lifetime adversities and the genetic background has been previously examined on a variety of measures of depression; however, only few studies have focused on major depression disorder (MDD) in adolescence. Using clinical data and DNA samples from mouthwash gathered from an epidemiological study on the prevalence of mental disorders in youths between 12 and 17 years old, we tested the statistical interaction between a set of psychosocial adversities experienced during childhood (CAs) with two common polymorphisms in the brain-derived neurotrophic factor (BDNF) (Val66Met) and SLC6A4 (L/S) genes on the probability of suffering MDD in adolescence. Genotype or allele frequencies for both polymorphisms were similar between groups of comparison (MDD N = 246; controls N = 270). The CAs factors: Abuse, neglect, and family dysfunctions; parental maladjustment, parental death, and to have experienced a life-threatening physical illness were predictors of clinical depression in adolescents. Remarkably, the cumulative number of psychosocial adversities was distinctly associated with an increase in the prevalence of depression but only in those Val/Val BDNF individuals; while the possession of at least a copy of the BDNF Met allele (i.e., Met +) was statistically linked with a "refractory" or resilient phenotype to the noticeable influence of CAs. Liability or resilience to develop MDD in adolescence is dependent of a complex interplay between particular environmental exposures and a set of plasticity genes including BDNF. A better understanding of these factors is important for developing better prevention and early intervention measures.

Interaction between BDNF Polymorphism and Physical Activity on Inhibitory Performance in the Elderly without Cognitive Impairment.

PubMed

Canivet, Anne; Albinet, Cédric T; Rodríguez-Ballesteros, Montserrat; Chicherio, Christian; Fagot, Delphine; André, Nathalie; Audiffren, Michel

2017-01-01

Background: In the elderly, physical activity (PA) enhances cognitive performances, increases brain plasticity and improves brain health. The neurotrophic hypothesis is that the release of brain-derived neurotrophic factor (BDNF), which is implicated in brain plasticity and cognition, is triggered by PA because motoneurons secrete BDNF into the bloodstream during exercise. Individual differences in cognitive performance may be explained by individual differences in genetic predisposition. A single nucleotide polymorphism on the BDNF gene, BDNF Val66Met, affects activity-dependent BDNF secretion. This study investigated the influence of the BDNFVal66Met polymorphism on the relationship between PA and controlled inhibition performance in older adults. Methods: A total of 114 healthy elderly volunteers (mean age = 71.53 years old) were evaluated. Participants were genotyped for the BDNFVal66Met polymorphism. We evaluated inhibitory performance using choice reaction times (RT) and error rates from a Simon-like task and estimated their PA using two self-reported questionnaires. We established four groups according to PA level (active vs. inactive) and BDNFVal66Met genotype (Met carriers vs. Val-homozygous). The results were analyzed using ANOVA and ANCOVA, including age, gender and body mass index as covariates. Results: The BDNFVal66Met polymorphism interacted with PA on controlled inhibition performance. More specifically, inactive Val-homozygous participants exhibited a lower inhibition performance than active Val homozygotes and inactive Met carriers; the former had a higher error rate without differences in RT. Conclusion: Differences between individuals on inhibitory performance may be partially understood by the interaction between genetic influence in BDNF secretion and PA level. The results of this study clearly support the neurotrophic hypothesis that BDNF synthesis is an important mechanism underlying the influence of physical activity on brain structure and

Pilot Study and Review: Physiological Differences in BDNF, a Potential Biomarker in Males and Females with Autistic Disorder.

PubMed

Spratt, Eve G; Granholm, Ann-Charlotte; Carpenter, Laura A; Boger, Heather A; Papa, Carrie E; Logan, Sarah; Chaudhary, Humera; Boatwright, Sarah-Wade; Brady, Kathleen T

There is a need for more biologic research in autistic disorder (AD) to determine if biomarkers exist that would be useful for correlating to symptom severity and/or clinical improvement during treatment. Given the fact that AD is 4 times more common in males than females, gender differences in physiological biomarkers may be present. One potential biomarker that has begun to be studied is brain-derived neurotropic factor (BDNF), a peptide involved in the regulation of neuronal cell survival, differentiation, and plasticity, and possessing an ability to influence neurotransmitter systems by modulating gene expression. This pilot study examined whether serum BDNF differed according to gender in children with AD and whether differences were associated with a behavioral phenotype or severity of illness. Data for this investigation were collected during the participants' baseline visit of an intervention study. Participants were males (n=29) and females (n=7), aged 5 to 12 years diagnosed with AD. Baseline serum BDNF concentration was determined for comparison to clinical ratings using an autism severity measure and the Pervasive Developmental Disorder-Behavior Inventory (PDD-BI). BDNF serum concentrations were higher in females (p<0.049). The baseline BDNF value corresponded significantly to hyperactivity in females (p<0.0002) but not in males. BDNF did not correlate with severity of disease in either gender. Although this is a small study, a better understanding of the central role of BDNF may provide insight into the pathophysiology of the disease and elucidate why gender differences exist in prevalence and behavioral phenotype of AD.

Huntingtin protein: A new option for fixing the Huntington's disease countdown clock.

PubMed

Caterino, Marco; Squillaro, Tiziana; Montesarchio, Daniela; Giordano, Antonio; Giancola, Concetta; Melone, Mariarosa A B

2018-06-01

Huntington's disease is a dreadful, incurable disorder. It springs from the autosomal dominant mutation in the first exon of the HTT gene, which encodes for the huntingtin protein (HTT) and results in progressive neurodegeneration. Thus far, all the attempted approaches to tackle the mutant HTT-induced toxicity causing this disease have failed. The mutant protein comes with the aberrantly expanded poly-glutamine tract. It is primarily to blame for the build-up of β-amyloid-like HTT aggregates, deleterious once broadened beyond the critical ∼35-37 repeats threshold. Recent experimental findings have provided valuable information on the molecular basis underlying this HTT-driven neurodegeneration. These findings indicate that the poly-glutamine siding regions and many post-translation modifications either abet or counter the poly-glutamine tract. This review provides an overall, up-to-date insight into HTT biophysics and structural biology, particularly discussing novel pharmacological options to specifically target the mutated protein and thus inhibit its functions and toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Levels of BDNF Impact Oligodendrocyte Lineage Cells Following a Cuprizone Lesion

PubMed Central

VonDran, Melissa W.; Singh, Harmandeep; Honeywell, Jean Z.; Dreyfus, Cheryl F.

2011-01-01

Previous work in culture has shown that basal forebrain (BF) oligodendrocyte (OLG) lineage cells respond to BDNF by increasing DNA synthesis and differentiation. Further, in the BF in vivo, reduced levels of BDNF as seen in BDNF +/− mice result in reduced numbers of NG2+ cells and deficits in myelin proteins throughout development and in the adult, suggesting that BDNF impacts the proliferating population of OLGs as well as differentiation in vivo. In this study, to investigate roles BDNF may play in the repair of a demyelinating lesion, the cuprizone model was used and the corpus callosum was examined. BDNF protein levels were reduced after cuprizone, suggesting that the demyelinating lesion, itself, elicits a decrease in BDNF. To analyze effects of a further reduction of BDNF on OLG lineage cells following cuprizone, BDNF +/− mice were evaluated. These mice exhibited a blunted increase in the NG2 response at 4 and 5 weeks of cuprizone. In addition, BDNF +/− mice exhibited decreased levels of myelin proteins during the demyelination and remyelination processes with no change in the total number of OLGs. These effects appear to be relatively specific to OLG lineage cells as comparable changes in CD11b+ microglia, GFAP+ astrocytes, and SMI32+ injured axons were not observed. These data indicate that BDNF may play a role following a demyelinating lesion, by regulating numbers of progenitors and the abilities of demyelinating and differentiating cells to express myelin proteins. PMID:21976503

Decreased Plasma BDNF Levels of Patients with Somatization Disorder

PubMed Central

Kang, Nam-In; Park, Jong-Il

2016-01-01

Objective Brain-derived neurotrophic factor (BDNF), one of the most abundant and important neurotrophins, is known to be involved in the development, survival, maintenance, and plasticity of neurons in the nervous system. Some studies have suggested that BDNF may play a role in the pathophysiology of several psychiatric illnesses such as depression and schizophrenia. Similarly, it is likely that the alteration of BDNF may be associated with the neuro-modulation that contributes to the development of somatization disorder. Methods The purpose of this study was to determine whether there is an abnormality of plasma BDNF levels in patients with somatization disorder, and to analyze the nature of the alteration after pharmacotherapy using an enzyme-linked immunosorbent assay (ELISA). Results The plasma BDNF levels of the patients with a somatization disorder were significantly lower compared with those of the control volunteers (83.61±89.97 pg/mL vs. 771.36±562.14 pg/mL); moreover, the plasma BDNF levels of those patients who received an antidepressant were significantly increased after the treatment (118.13±91.45 pg/mL vs. 72.92±88.21 pg/mL). Conclusion These results suggest that BDNF may play a role in the pathophysiology of somatization disorder. PMID:27757131

Mosquito Cellular Factors and Functions in Mediating the Infectious entry of Chikungunya Virus

PubMed Central

Lee, Regina Ching Hua; Hapuarachchi, Hapuarachchige Chanditha; Chen, Karen Caiyun; Hussain, Khairunnisa' Mohamed; Chen, Huixin; Low, Swee Ling; Ng, Lee Ching; Lin, Raymond; Ng, Mary Mah-Lee; Chu, Justin Jang Hann

2013-01-01

Chikungunya virus (CHIKV) is an arthropod-borne virus responsible for recent epidemics in the Asia Pacific regions. A customized gene expression microarray of 18,760 transcripts known to target Aedes mosquito genome was used to identify host genes that are differentially regulated during the infectious entry process of CHIKV infection on C6/36 mosquito cells. Several genes such as epsin I (EPN1), epidermal growth factor receptor pathway substrate 15 (EPS15) and Huntingtin interacting protein I (HIP1) were identified to be differentially expressed during CHIKV infection and known to be involved in clathrin-mediated endocytosis (CME). Transmission electron microscopy analyses further revealed the presence of CHIKV particles within invaginations of the plasma membrane, resembling clathrin-coated pits. Characterization of vesicles involved in the endocytic trafficking processes of CHIKV revealed the translocation of the virus particles to the early endosomes and subsequently to the late endosomes and lysosomes. Treatment with receptor-mediated endocytosis inhibitor, monodansylcadaverine and clathrin-associated drug inhibitors, chlorpromazine and dynasore inhibited CHIKV entry, whereas no inhibition was observed with caveolin-related drug inhibitors. Inhibition of CHIKV entry upon treatment with low-endosomal pH inhibitors indicated that low pH is essential for viral entry processes. CHIKV entry by clathrin-mediated endocytosis was validated via overexpression of a dominant-negative mutant of Eps15, in which infectious entry was reduced, while siRNA-based knockdown of genes associated with CME, low endosomal pH and RAB trafficking proteins exhibited significant levels of CHIKV inhibition. This study revealed, for the first time, that the infectious entry of CHIKV into mosquito cells is mediated by the clathrin-dependent endocytic pathway. PMID:23409203

Association of COMT (Val158Met) and BDNF (Val66Met) gene polymorphisms with anxiety, ADHD and tics in children with autism spectrum disorder.

PubMed

Gadow, Kenneth D; Roohi, Jasmin; DeVincent, Carla J; Kirsch, Sarah; Hatchwell, Eli

2009-11-01

The aim of the study is to examine rs4680 (COMT) and rs6265 (BDNF) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total sample of 67 children with autism spectrum disorder (ASD). Both COMT (p = 0.06) and BDNF (p = 0.07) genotypes were marginally significant for teacher ratings of social phobia (etap (2) = 0.06). Analyses also indicated associations of BDNF genotype with parent-rated ADHD (p = 0.01, etap (2) = 0.10) and teacher-rated tics (p = 0.04; etap (2) = 0.07). There was also evidence of a possible interaction (p = 0.02, etap (2) = 0.09) of BDNF genotype with DAT1 3' VNTR with tic severity. BDNF and COMT may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples.

Direct Interaction between Scaffolding Proteins RACK1 and 14-3-3ζ Regulates Brain-derived Neurotrophic Factor (BDNF) Transcription*

PubMed Central

Neasta, Jérémie; Kiely, Patrick A.; He, Dao-Yao; Adams, David R.; O'Connor, Rosemary; Ron, Dorit

2012-01-01

RACK1 is a scaffolding protein that spatially and temporally regulates numerous signaling cascades. We previously found that activation of the cAMP signaling pathway induces the translocation of RACK1 to the nucleus. We further showed that nuclear RACK1 is required to promote the transcription of the brain-derived neurotrophic factor (BDNF). Here, we set out to elucidate the mechanism underlying cAMP-dependent RACK1 nuclear translocation and BDNF transcription. We identified the scaffolding protein 14-3-3ζ as a direct binding partner of RACK1. Moreover, we found that 14-3-3ζ was necessary for the cAMP-dependent translocation of RACK1 to the nucleus. We further observed that the disruption of RACK1/14-3-3ζ interaction with a peptide derived from the RACK1/14-3-3ζ binding site or shRNA-mediated 14-3-3ζ knockdown inhibited cAMP induction of BDNF transcription. Together, these data reveal that the function of nuclear RACK1 is mediated through its interaction with 14-3-3ζ. As RACK1 and 14-3-3ζ are two multifunctional scaffolding proteins that coordinate a wide variety of signaling events, their interaction is likely to regulate other essential cellular functions. PMID:22069327