Alterations In Brain-derived Neurotrophic Factor Expression Research Articles

Biomarkers of Depression among Adolescent Girls: BDNF and Epigenetics.

Alterations in brain-derived neurotrophic factor (BDNF) expression have been suggested to mediate the influence of environmental factors on the emergence of depression through epigenetic modifications. However, research on this subject in the developmental population is lacking and the pathophysiology of adolescent depression remains unclear. We aimed to investigate the alterations in BDNF expression and global DNA methylation in depression among adolescent girls. Thirty female inpatients with the initial diagnosis of depression were assessed before and after the period of antidepressant treatment and compared with thirty age-matched healthy controls. The assessment involved BDNF and proBDNF serum levels, the BDNF gene exon IV promoter methylation, and global DNA methylation. The methylation level in the BDNF gene exon IV promoter was significantly lower in the studied group compared with the control and correlated negatively with the severity of depression. The test distinguished the studied group from the controls with a sensitivity of 37% and specificity of 90%. The differences were no longer present after the period of antidepressant treatment. No differences in the global DNA methylation, BDNF, and proBDNF levels were found. We concluded that decreased methylation in the BDNF exon IV promoter could be considered as a biomarker of a depression state among adolescent girls.

Association of plasma BDNF levels with different stages of Alzheimer’s disease: a cross-sectional study

ABSTRACT Background Growing evidence shows that the expression of brain-derived neurotrophic factor (BDNF) is altered in the peripheral blood of participants with Alzheimer’s disease (AD). It is unclear, however, whether altered BDNF expression is also observed in the early stages of AD. Methods In the present study, 138 normal controls (NC), 57 participants with subjective cognitive decline (SCD), and 37 participants with amnestic mild cognitive impairment (aMCI) and AD were included. Plasma BDNF protein levels were assessed using a commercial multiplex Luminex-based kit. Patient samples were also probed for the presence of BDNF gene variant rs6265. Results Pairwise comparisons between the groups showed that there was not a significant difference in BDNF levels when comparing SCD with NC and when comparing SCD with aMCI/AD, but BDNF levels in aMCI/AD samples were increased when compared with NC samples. For models differentiating clinical groups, discriminant analysis was performed by including education, APOE genotype, and BDNF levels in the model. This approach distinguishes participants with SCD (AUC = 0.630) and aMCI/AD (AUC = 0.665) from NC. Conclusion Our results suggest that expression of BDNF in plasma is altered at the clinical stage of AD.

A key role of miR-132-5p in the prefrontal cortex for persistent prophylactic actions of (R)-ketamine in mice

(R,S)-ketamine is known to elicit persistent prophylactic effects in rodent models of depression. However, the precise molecular mechanisms underlying its action remain elusive. Using RNA-sequencing analysis, we searched for novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R,S)-ketamine in chronic restraint stress (CRS) model. Pretreatment with (R)-ketamine (10 mg/kg, 1 day before CRS) significantly ameliorated body weight loss, increased immobility time of forced swimming test, and decreased sucrose preference of sucrose preference test in CRS-exposed mice. RNA-sequencing analysis of prefrontal cortex (PFC) revealed that several miRNAs such as miR-132-5p might contribute to sustained prophylactic effects of (R)-ketamine. Methyl CpG binding protein 2 (MeCP2) is known to regulate brain-derived neurotrophic factor (BDNF) expression. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated altered expression of miR-132-5p and its regulated genes (Bdnf, Mecp2, Tgfb1, Tgfbr2) in the PFC of CRS-exposed mice. Furthermore, (R)-ketamine significantly attenuated altered expression of BDNF, MeCP2, TGF-β1 (transforming growth factor β1), and synaptic proteins (PSD-95, and GluA1) in the PFC of CRS-exposed mice. Administration of agomiR-132-5p decreased the expression of Bdnf and Tgfb1 in the PFC, resulting in depression-like behaviors. In contrast, administration of antagomiR-132-5p blocked the increased expression of miR-132-5p and decreased expression of Bdnf in the PFC of CRS-exposed mice, resulting in antidepressant-like effects. In conclusion, our data show a novel role of miR-132-5p in the PFC underlying depression-like phenotypes in CRS model and the sustained prophylactic effects of (R)-ketamine.

Cognitive Dysfunction in a Mouse Model of Cerebral Ischemia Influences Salivary Metabolomics.

Vascular dementia, caused by cerebrovascular disease, is associated with cognitive impairment and reduced hippocampal metabolite levels. Specifically, cognitive impairment can be induced by decreased hippocampal brain-derived neurotrophic factor (BDNF) expression. The development of low or non-invasive biomarkers to characterize these diseases is an urgent task. Disturbance of metabolic pathways has been frequently observed in cognitive impairment, and salivary molecules also showed the potentials to reflect cognitive impairment. Therefore, we evaluated salivary metabolic profiles associated with altered hippocampal BDNF expression levels in a cerebral ischemia mouse model using metabolomic analyses. The effect of tacrine (a cholinesterase inhibitor) administration was also examined. The arteries of ICR mice were occluded with aneurysm clips to generate the cerebral ischemia model. Learning and memory performance was assessed using the elevated plus maze (EPM) test. Hippocampal and blood BDNF levels were quantified using an enzyme-linked immunosorbent assay. Glutamate decarboxylase 1 (GAD1) mRNA expression, is associated with cognitive impairment, was quantified by a real-time polymerase chain reaction. The EPM test revealed impaired spatial working memory in the cerebral ischemia mouse model; tacrine administration ameliorated this memory impairment. Cerebral ischemia suppressed GAD1 expression by decreasing hippocampal BDNF expression. In total, seven salivary metabolites, such as trimethylamine N-oxide and putrescine, were changed by cognitive impairment and tacrine administration. Our data suggest that salivary metabolite patterns were associated with cognitive function.

The Relationships Between Stress, Mental Disorders, and Epigenetic Regulation of BDNF.

Brain-derived neurotrophic factor (BDNF), a critical member of the neurotrophic family, plays an important role in multiple stress-related mental disorders. Although alterations in BDNF in multiple brain regions of individuals experiencing stress have been demonstrated in previous studies, it appears that a set of elements are involved in the complex regulation. In this review, we summarize the specific brain regions with altered BDNF expression during stress exposure. How various environmental factors, including both physical and psychological stress, affect the expression of BDNF in specific brain regions are further summarized. Moreover, epigenetic regulation of BDNF, including DNA methylation, histone modification, and noncoding RNA, in response to diverse types of stress, as well as sex differences in the sensitivity of BDNF to the stress response, is also summarized. Clarification of the underlying role of BDNF in the stress process will promote our understanding of the pathology of stress-linked mental disorders and provide a potent target for the future treatment of stress-related illness.

Microglial activation contributes to depressive-like behavior in dopamine D3 receptor knockout mice

We previously demonstrated that the dopamine D3 receptor (D3R) inhibitor, NGB2904, increases susceptibility to depressive-like symptoms, elevates pro-inflammatory cytokine expression, and alters brain-derived neurotrophic factor (BDNF) levels in mesolimbic dopaminergic regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and ventral tegmental area (VTA) in mice. The mechanisms by which D3R inhibition affects neuroinflammation and onset of depression remain unclear. Here, using D3R-knockout (D3RKO) and congenic wild-type C56BL/6 (WT) mice, we demonstrated that D3RKO mice displayed depressive-like behaviors, increased tumornecrosisfactor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels, and altered BDNF expression in selected mesolimbic dopaminergic regions. D3R expression was localized to astrocytes or microglia in the mPFC, NAc, and VTA in WT mice. D3RKO mice exhibited a large number of Iba1-labelled microglia in the absence of glial fibrillary acidic protein (GFAP)-labelled astrocytes in mesolimbic dopaminergic brain areas. Inhibition or ablation of microglia by minocycline (25 mg/kg and 50 mg/kg) or PLX3397 (40 mg/kg) treatment ameliorated depressive-like symptoms, alterations in pro-inflammatory cytokine levels, and BDNF expression in the indicated brain regions in D3RKO mice. Minocycline therapy alleviated the increase in synaptic density in the NAc in D3RKO mice. These findings suggest that microglial activation in selected mesolimbic reward regions affects depressive-like behaviors induced by D3R deficiency.

Brain Derived Neurotrophic Factor (BDNF) Delays Onset of Pathogenesis in Transgenic Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1).

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin-1 (ATXN1) gene and characterized by motor deficits and cerebellar neurodegeneration. Even though mutant ATXN1 is expressed from an early age, disease onset usually occurs in patient’s mid-thirties, indicating the presence of compensatory factors that limit the toxic effects of mutant ATXN1 early in disease. Brain derived neurotrophic factor (BDNF) is a growth factor known to be important for the survival and function of cerebellar neurons. Using gene expression analysis, we observed altered BDNF expression in the cerebella of Purkinje neuron specific transgenic mouse model of SCA1, ATXN1[82Q] mice, with increased expression during the early stage and decreased expression in the late stage of disease. We therefore investigated the potentially protective role of BDNF in early stage SCA1 through intraventricular delivery of BDNF via ALZET osmotic pumps. Extrinsic BDNF delivery delayed onset of motor deficits and Purkinje neuron pathology in ATXN1[82Q] mice supporting its use as a novel therapeutic for SCA1.

Cannabinoids prevent depressive-like symptoms and alterations in BDNF expression in a rat model of PTSD

Posttraumatic stress disorder (PTSD) is a debilitating condition highly comorbid with depression. The endocannabinoid (eCB) system and brain-derived neurotrophic factor (BDNF) are suggestively involved in both disorders. We examined whether cannabinoids can prevent the long-term depressive-like symptoms induced by exposure to the shock and situational reminders (SRs) model of PTSD.The CB1/2 receptor agonist WIN55,212-2 (0.5 mg/kg; i.p.), the fatty acid hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg, i.p.) or vehicle were administered 2 h after severe shock. Cannabinoids prevented the shock/SRs-induced alterations in social recognition memory, locomotion, passive coping, anxiety-like behavior, anhedonia, fear retrieval, fear extinction and startle response as well as the decrease in BDNF levels in the hippocampus and prefrontal cortex (PFC). Furthermore, significant correlations were found between depressive-like behaviors and BDNF levels in the brain. The findings suggest that cannabinoids may prevent both depressive- and PTSD-like symptoms following exposure to severe stress and that alterations in BDNF levels in the brains' fear circuit are involved in these effects.

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

BackgroundHuntington 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.ObjectiveThis 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.MethodsAnimals 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.ResultsIn 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 seemed to show a mild deficit in preference for social novelty, but no changes in social interest. Molecular analyses revealed that BACHD animals exposed to the social interaction test displayed decreased mRNA levels of the total form of BDNF in ventral striatum and unaltered striatal expression of D1 and D2 dopamine receptors.ConclusionsTaken together, these results indicate deficits in several parameters representative of sociability. Altered BDNF expression in the ventral striatum may contribute to the deficits in sociability in 8 months old BACHD rats. These data support the validity of the BACHD rat model in mimicking features of certain social deficits that could be relevant to symptoms in patients.

Assessment of a combination of Serum Proteins as potential biomarkers to clinically predict Schizophrenia.

Schizophrenia (SZ) is a devastating psychiatric disorder. Validation of potential serum biomarkers during first-episode psychosis (FEP) is especially helpful to understand the onset and prognosis of this disorder. To address this question, we examined multiple blood biomarkers and assessed the efficacy to diagnose SZ. The expression levels of Neuregulin1 (NRG1), ErbB4, brain-derived neurotrophic factor (BDNF), DNA methyltransferases 1 (DNMT1) and ten-eleven translocation 1 (TET1) proteins in peripheral blood of 53 FEP patients and 57 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA). Multivariable logistic regression including biomarker concentration as covariates was used to predict SZ. Differentiating performance of these five serum protein levels was analyzed by Receiver Operating Characteristic (ROC) curve analysis. We found that patients with SZ present a higher concentration of DNMT1, and TET1 in peripheral blood, but a lower concentration of NRG1, ErbB4 and BDNF than controls. Multivariable logistic regression showed that ErbB4, BDNF and TET1 were independent predictors of SZ, and when combined, provided high diagnostic accuracy for SZ. Together, our findings highlight that altered expression of NRG1, ErbB4, BDNF, DNMT1 and TET1 are involved in schizophrenia development and they may serve as potential biomarkers for the diagnosis of the schizophrenia. Therefore, our study provides evidence that combination of ErbB4, BDNF and TET1 biomarkers could greatly improve the diagnostic performance.

The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review.

There is evidence that development and maintenance of neural connections are disrupted in major mental disorders, which indicates that neurotrophic factors could play a critical role in their pathogenesis. Stress is a well-established risk factor for psychopathology and recent research suggests that disrupted signaling via brain-derived neurotrophic factor (BDNF) may be involved in mediating the negative effects of stress on the brain. Social isolation of rats elicits chronic stress and is widely used as an animal model of mental disorders such as schizophrenia and depression. We carried out a systematic search of published studies to review current evidence for an altered expression of BDNF in the brain of rats reared or housed in social isolation. Across all age groups (post-weaning, adolescent, adult), majority of the identified studies (16/21) reported a decreased expression of BDNF in the hippocampus. There are far less published data on BDNF expression in other brain regions. Data are also scarce to assess the behavioral changes as a function of BDNF expression, but the downregulation of BDNF seems to be associated with increased anxiety-like symptoms. The reviewed data generally support the putative involvement of BDNF in the pathogenesis of stress-related mental illness. However, the mechanisms linking chronic social isolation, BDNF expression and the elicited behavioral alterations are currently unknown.

Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder.

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD-related phenotypes with particular emphasis on social behavior and cognition in Shank1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, Shank1-/- null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain-derived neurotrophic factor (BDNF) protein expression in the hippocampus of Shank1-/- mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in Shank1-/- mice, consistent with increased learning-associated BDNF. Together, our findings indicate that Shank1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target.

Gender Peculiarities of Postresuscitation in the Expression of Brain-Derived Neurotrophic Factor (BDNF)

Purpose : to identify gender peculiarities of postresuscitation shifts in BDNF expression and neuronal death. Materials and Methods . At different points of the postresuscitation period (days 1-, 4-, 7-, and 14), the condition of highly sensitive to hypoxia neuronal populations (pyramidal neurons of hippocampus and Purkinje cells of cerebellum) were studied in white mature female rats exposed to a 10-minute stop of systemic blood circulation (compression of vascular fascicle of the heart). Sham operated animals were used as the control. Immunohistochemical detection of BDNF-immunoreactive neurons followed with determination of optical density, number of cells with different levels of BDNF expression, and total count of neurons per 1 mm of the length of their layer was carried out. The work was done using the image analysis system (computer Intel, microscope Olympus BX-41, software ImadgeScopeM, ImageJ 1,48v, Excel 2007). Statistic processing of data was performed with the aid of Statistica 7.0 using Kolmogorov-Smirnov λ test, Mann-Whitney U test, and Student's t-test. Results . The dynamics of postresuscitation shifts in BDNF-immunoreactivity of neuronal populations highly sensitive to hypoxia was studied in rats. Purkinje cells population in tissue slides from brain specimens harvested from female rats the alterations in BDNF expression became evident. This pattern was accompanied by the death of neurons. Those shifts in female animals were found to develop later than in male rats — by day 7 of the postresuscitation. Only BDNF-negative and BDNF-weakly positive neurons not survived postresuscitation. In the population of pyramidal cells of hippocampus in females, in contrast to males, there were no quantitative changes in BDNF molecules as revealed by immunohistochemistry and neuronal death process did not develop. Conclusion . Gender peculiarities in the development of postresuscitation shifts in BDNF expression and associated therewith death of neurons were revealed. It was shown that after cardiac arrest of the same duration, the postresuscitation shifts in BDNF expression and neuronal death manifested mostly in males compared to females. At the same time, animals of both genders demonstrate common postresuscitation brain alterations evidencing connection between the level of BDNF expression in neurons and their resistance to ischemia-reperfusion. Gender-specific patterns of brain damage and their importance for understanding the mechanisms of post-hypoxic encephalopathies are discussed.

Effects of early neonatal proinflammatory stress on the expression of BDNF transcripts in the brain regions of prepubertal male rats

Early postnatal proinflammatory stress may evoke behavioral impairments in adulthood; however, the underlying mechanisms are still elusive. The brain-derived neurotrophic factor (BDNF) plays a key role in neuroplastic changes in health, as well as in pathology. The BDNF gene is transcribed to exon-specific mRNAs and the pattern of their expression depends on stimulus. We suggested that disturbances of the exonspecific BDNF mRNA expression in the brain regions after stress induced by proinflammatory stimuli in the early postnatal period could be one of the underlying mechanisms of consequent behavioral impairments. Thus, the aim of the study was to examine the effects of proinflammatory stress in early postnatal ontogeny on the BDNF polypeptide content and the patterns of expression of the BDNF gene in the neocortex and hippocampus of prepubertal male rats. The proinflammatory stress was induced by the subcutaneous administration of bacterial lipopolysaccharide (LPS) to rat pups on postnatal days 3 and 5, while BDNF expression was studied in 36-day-old rats. The BDNF polypeptide content was estimated using an enzyme-linked immunosorbent assay, while a quantitative polymerase chain reaction followed by reverse transcription was used to detect the exon-specific BDNF mRNA expression. The levels of BDNF and its transcripts, containing the common exon IX were similar in the control and LPS-treated rats. In the rats treated with LPS, the level of BDNF mRNA containing exon IV was lower in the neocortex but not in the hippocampus. No changes in the expression of the transcripts containing exons I and VI were observed in any of the brain structures studied. We suggest that specific alterations in BDNF expression may be involved in susceptibility to the development of behavioral impairments of animals subjected to early proinflammatory stress.

Cellular and molecular mechanisms of the brain-derived neurotrophic factor in physiological and pathological conditions.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in the central nervous system, promoting synaptic plasticity, neurogenesis and neuroprotection. The BDNF gene structure is very complex and consists of multiple 5'-non-coding exons, which give rise to differently spliced transcripts, and one coding exon at the 3'-end. These multiple transcripts, together with the complex transcriptional regulatory machinery, lead to a complex and fine regulation of BDNF expression that can be tissue and stimulus specific. BDNF effects are mainly mediated by the high-affinity, tropomyosin-related, kinase B receptor and involve the activation of several downstream cascades, including the mitogen-activated protein kinase, phospholipase C-γ and phosphoinositide-3-kinase pathways. BDNF exerts a wide range of effects on neuronal function, including the modulation of activity-dependent synaptic plasticity and neurogenesis. Importantly, alterations in BDNF expression and function are involved in different brain disorders and represent a major downstream mechanism for stress response, which has important implications in psychiatric diseases, such as major depressive disorders and schizophrenia. In the present review, we have summarized the main features of BDNF in relation to neuronal plasticity, stress response and pathological conditions, and discussed the role of BDNF as a possible target for pharmacological and non-pharmacological treatments in the context of psychiatric illnesses.

Effects of Duloxetine Treatment on Cognitive Flexibility and BDNF Expression in the mPFC of Adult Male Mice Exposed to Social Stress during Adolescence

Early stress is a significant risk factor for the onset of mood disorders such as depression during adulthood. Impairments in cognitive flexibility mediated by prefrontal cortex (PFC) dysfunction are increasingly recognized as important etiological and pathological factors in the development of depression. Our previous study demonstrated that social defeat stress during early adolescence produced delayed deficits in cognitive flexibility in adult mice. The potential molecular mechanisms underlying these long-term consequences remain unclear. One candidate molecule is brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity. In this study, we initially examined the effects of adolescent social stress on cognitive flexibility and PFC BDNF expression within a week after the last stress exposure and 6 weeks later during adulthood. Adolescent (PND 28) male mice were subjected to stress or control manipulation for 10 days. The attentional set-shifting task (AST) was used to assess cognitive flexibility. Levels of BDNF mRNA and protein in the PFC were examined after behavioral testing. The results demonstrated that previously stressed mice exhibited delayed extra-dimensional set-shifting deficits in AST when tested as adults but not when tested as adolescents. Consistent with the cognitive alterations, adolescent stress induced dynamic alterations in BDNF expression in the medial PFC (mPFC), with a transient increase observed shortly after the stress, followed by a decrease 6 weeks later during adulthood. Next, we further determined the effects of chronic treatment with the antidepressant duloxetine during early adulthood on cognitive and molecular alterations induced by adolescent stress. Compared with the controls, duloxetine treatment reversed the cognitive deficits and increased the BDNF protein expression in the mPFC during adulthood in previously stressed mice. These findings demonstrated that BDNF expression in the mPFC was sensitive to adolescent social stress, which may contribute to the disturbance of the development and later functioning of this brain region.

The Role of BDNF in the Development of Fear Learning.

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.

Effects of early neonatal proinflammatory stress on the expression of BDNF transcripts in the brain regions of prepubertal male rats

Early postnatal proinflammatory stress provokes behavioral impairments in adulthood; however, underlying mechanisms are still elusive. Brain-derived neurotrophic factor (BDNF) plays a crucial role in neuroplastic changes in health as well as at pathology. The BDNF gene is transcribed to exon-specific mRNAs and the pattern of their expression depends on stimulus. We suggest that disturbances of exonspecific BDNF mRNA expression in the brain regions after stress induced by proinflammatory stimuli in early postnatal period could be one of the underlying mechanisms of consequent behavioral impairments. Thus, the aim of the study was to investigate the effects of proinflammatory stress in early postnatal ontogeny on the expression of BDNF and the patterns of expression of the BDNF gene in the neocortex and hippocampus of prepubertal male rats. The proinflammatory stress was induced by subcutaneous administration of bacterial lipopolysaccharide (LPS) to rat pups on postnatal days 3 and 5, while BDNF expression was analyzed in 36-day-old rats. BDNF polypeptide concentration was estimated by means of an enzyme-linked immunosorbent assay, while quantitative polymerase chain reaction followed by reverse transcription was used to detect exon-specific BDNF mRNA expression. The levels of BDNF and transcripts, containing common exon IX were similar in the control and LPS-treated rats. In the rats treated with LPS, the level of BDNF mRNA, containing exon IV, was lower in the neocortex, but not in the hippocampus. No changes in the expression of the transcripts containing exons I and VI were observed in any brain structure studied. We suggest that specific alterations in BDNF expression may be involved in the susceptibility to the development of behavioral impairments of animals subjected to early proinflammatory stress.

Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice

Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2−/−) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2−/− forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2−/− mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2−/− mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2−/− mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2−/− forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.

Down-regulation of BDNF in cell and animal models increases striatal-enriched protein tyrosine phosphatase 61 (STEP61 ) levels.

Brain-derived neurotrophic factor (BDNF) regulates synaptic strengthening and memory consolidation, and altered BDNF expression is implicated in a number of neuropsychiatric and neurodegenerative disorders. BDNF potentiates N-methyl-D-aspartate receptor function through activation of Fyn and ERK1/2. STriatal-Enriched protein tyrosine Phosphatase (STEP) is also implicated in many of the same disorders as BDNF but, in contrast to BDNF, STEP opposes the development of synaptic strengthening. STEP-mediated dephosphorylation of the NMDA receptor subunit GluN2B promotes internalization of GluN2B-containing NMDA receptors, while dephosphorylation of the kinases Fyn, Pyk2, and ERK1/2 leads to their inactivation. Thus, STEP and BDNF have opposing functions. In this study, we demonstrate that manipulation of BDNF expression has a reciprocal effect on STEP61 levels. Reduced BDNF signaling leads to elevation of STEP61 both in BDNF(+/-) mice and after acute BDNF knockdown in cortical cultures. Moreover, a newly identified STEP inhibitor reverses the biochemical and motor abnormalities in BDNF(+/-) mice. In contrast, increased BDNF signaling upon treatment with a tropomyosin receptor kinase B agonist results in degradation of STEP61 and a subsequent increase in the tyrosine phosphorylation of STEP substrates in cultured neurons and in mouse frontal cortex. These findings indicate that BDNF-tropomyosin receptor kinase B signaling leads to degradation of STEP61 , while decreased BDNF expression results in increased STEP61 activity. A better understanding of the opposing interaction between STEP and BDNF in normal cognitive functions and in neuropsychiatric disorders will hopefully lead to better therapeutic strategies. Altered expression of BDNF and STEP61 has been implicated in several neurological disorders. BDNF and STEP61 are known to regulate synaptic strengthening, but in opposite directions. Here, we report that reduced BDNF signaling leads to elevation of STEP61 both in BDNF(+/-) mice and after acute BDNF knockdown in cortical cultures. In contrast, activation of TrkB receptor results in the degradation of STEP61 and reverses hyperlocomotor activity in BDNF(+/-) mice. Moreover, inhibition of STEP61 by TC-2153 is sufficient to enhance the Tyr phosphorylation of STEP substrates and also reverses hyperlocomotion in BDNF(+/-) mice. These findings give us a better understanding of the regulation of STEP61 by BDNF in normal cognitive functions and in neuropsychiatric disorders.