Brain-derived Neurotrophic Factor In Females Research Articles

A sexually dimorphic signature of activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the prefrontal cortex.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. We and others hypothesize that diminished activity-dependent neural signaling is a common molecular pathway dysregulated in ASD caused by diverse genetic mutations. Brain-derived neurotrophic factor (BDNF) is a key growth factor mediating activity-dependent neural signaling in the brain. A common single nucleotide polymorphism (SNP) in the pro-domain of the human BDNF gene that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) significantly decreases activity-dependent BDNF release without affecting basal BDNF secretion. By using mice with genetic knock-in of this human BDNF methionine (Met) allele, our previous studies have shown differential severity of autism-like social deficits in male and female BDNF+/Met mice. Pyramidal neurons are the principal neurons in the prefrontal cortex (PFC), a key brain region for social behaviors. Here, we investigated the impact of diminished activity-dependent BDNF signaling on the intrinsic excitability of pyramidal neurons in the PFC. Surprisingly, diminished activity-dependent BDNF signaling significantly increased the intrinsic excitability of pyramidal neurons in male mice, but not in female mice. Notably, significantly decreased thresholds of action potentials were observed in male BDNF+/Met mice, but not in female BDNF+/Met mice. Voltage-clamp recordings revealed that the sodium current densities were significantly increased in the pyramidal neurons of male BDNF+/Met mice, which were mediated by increased transcriptional level of Scn2a encoding sodium channel NaV 1.2. Medium after hyperpolarization (mAHP), another important parameter to determine intrinsic neuronal excitability, is strongly associated with neuronal firing frequency. Further, the amplitudes of mAHP were significantly decreased in male BDNF+/Met mice only, which were mediated by the downregulation of Kcnn2 encoding small conductance calcium-activated potassium channel 2 (SK2). This study reveals a sexually dimorphic signature of diminished activity-dependent BDNF signaling on the intrinsic neuronal excitability of pyramidal neurons in the PFC, which provides possible cellular and molecular mechanisms underpinning the sex differences in idiopathic ASD patients and human autism victims who carry BDNF Val66Met SNP.

Short- and Long-Term Effects of Subchronic Stress Exposure in Male and Female Brain-Derived Neurotrophic Factor Knock-In Val66Met Mice.

Stress is an important risk factor for the onset of anxiety and depression. The ability to cope with stressful events varies among different subjects, probably depending on different genetic variants, sex and previous life experiences. The Val66Met variant of Brain-Derived Neurotrophic Factor (BDNF), which impairs the activity-dependent secretion of BDNF, has been associated with increased susceptibility to the development of various neuropsychiatric disorders. Adult male and female wild-type Val/Val (BDNFV/V) and heterozygous Val/Met (BDNFV/M) mice were exposed to two sessions of forced swimming stress (FSS) per day for two consecutive days. The mice were behaviorally tested 1 day (short-term effect) or 11 days (long-term effect) after the last stress session. Protein and mRNA levels were measured in the hippocampus 16 days after the end of stress exposure. Stressed mice showed a higher anxiety-like phenotype compared to non-stressed mice, regardless of the sex and genotype, when analyzed following the short period of stress. In the prolonged period, anxiety-like behavior persisted only in male BDNFV/M mice (p < 0.0001). Interestingly, recovery in male BDNFV/V mice was accompanied by an increase in pCREB (p < 0.001) and Bdnf4 (p < 0.01) transcript and a decrease in HDAC1 (p < 0.05) and Dnmt3a (p = 0.01) in the hippocampus. Overall, our results show that male and female BDNF Val66Met knock-in mice can recover from subchronic stress in different ways.

Impaired fear memory in a rat model of the brain-derived neurotrophic factor Val66Met polymorphism is reversed by chronic exercise

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with reduced activity-dependent BDNF release in the brain and has been implicated in fear and anxiety disorders, including post-traumatic stress disorder. Exercise has been shown to have benefits in affective disorders but the role of BDNF Val66Met remains unclear. Male and female BDNF Val66Met rats were housed in automated running-wheel cages from weaning while controls were housed in standard cages. During adulthood, all rats underwent standard three-day fear conditioning testing, with three tone/shock pairings on day 1 (acquisition), and extinction learning and memory (40 tones/session) on day 2 and day 3. Expression of BDNF and stress-related genes were measured in the frontal cortex. Extinction testing on day 2 revealed significantly lower freezing in response to initial cue exposure in control Met/Met rats, reflecting impaired fear memory. This deficit was reversed in both male and female Met/Met rats exposed to exercise. There were no genotype effects on acquisition or extinction of fear, however chronic exercise increased freezing in all groups at every stage of testing. Exercise furthermore led to increased expression of Bdnf in the prefrontal cortex of females and its isoforms in both sexes, as well as increased expression of FK506 binding protein 51 (Fkpb5) in females and decreased expression of Serum/glucocorticoid-regulated kinase (Sgk1) in males independent of genotype. These results show that the Met/Met genotype of the Val66Met polymorphism affects fear memory, and that chronic exercise selectively reverses this genotype effect. Chronic exercise also led to an overall increase in freezing in all genotypes which may contribute to results.

A Rat Model of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism Shows Attenuated Motivation for Alcohol Self-Administration and Diminished Propensity for Cue-Induced Relapse in Females.

Brain-derived neurotrophic factor (BDNF) has been implicated in alcohol use disorder. The Val66Met polymorphism is a common variant of the BDNF gene (rs6265) which reduces activity-dependent BDNF release, and has been suggested as a risk factor for psychiatric disorders and substance use. Using an operant self-administration paradigm, this study aimed to investigate ethanol preference and ethanol seeking in a novel rat model of the BDNF Val66Met polymorphism, Val68Met rats. Male and female BDNF Val68Met rats of three genotypes (Val/Val, Val/Met and Met/Met) were trained to lever press for a 10% ethanol solution. There was no effect of Val68Met genotype on acquisition of stable response to ethanol or its extinction. Met/Met rats of both sexes had a slight, but significantly lower breakpoint during progressive ratio sessions while female rats with the Met/Met genotype demonstrated a lower propensity for reinstatement of responding to cues. There were no effects of Val68Met genotype on anxiety-like behaviour or locomotor activity. In conclusion, Met/Met rats showed lower motivation to continue to press for a reward, and also a decreased propensity to relapse, suggesting a possible protective effect of the Met/Met genotype against alcohol use disorder, at least in females.

Diminished activity-dependent BDNF signaling differentially causes autism-like behavioral deficits in male and female mice.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. Recent human genetic studies have identified multiple high-risk genes for ASD, which produce similar phenotypes, indicating that diverse genetic factors converge to common molecular pathways. We and others have hypothesized that activity-dependent neural signaling is a convergent molecular pathway dysregulated in ASD. However, the causal link between diminished activity-dependent neural signaling and ASD remains unclear. Brain-derived neurotrophic factor (BDNF) is a key molecule mediating activity-dependent neural signaling. We therefore hypothesize that diminished activity-dependent BDNF signaling could confer autism-like behavioral deficits. Here, we investigated the effect of diminished activity-dependent BDNF signaling on autism-like behavioral deficits by using mice with genetic knock-in of a human BDNF methionine (Met) allele, which has decreased activity-dependent BDNF release without altering basal BDNF level. Compared with wild-type (WT) controls, diminished activity-dependent BDNF signaling similarly induced anxiety-like behaviors in male and female mice. Notably, diminished activity-dependent BDNF signaling differentially resulted in autism-like social deficits and increased self-grooming in male and female mice, and male mice were more severe than female mice. Again, sexually dimorphic spatial memory deficits were observed in female BDNF+/Met mice, but not in male BDNF+/Met mice. Our study not only reveals a causal link between diminished activity-dependent BDNF signaling and ASD-like behavioral deficits, but also identifies previously underappreciated sex-specific effect of diminished activity-dependent BDNF signaling in ASD. These mice with genetic knock-in of the human BDNF Met variant provide a distinct mouse model for studying the cellular and molecular mechanisms underlying diminished activity-dependent neural signaling, the common molecular pathway dysregulated in ASD.

Sex and BDNF Val66Met polymorphism matter for exercise-induced increase in neurogenesis and cognition in middle-aged mice

Females show greater benefits of exercise on cognition in both humans and rodents, which may be related to brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP), the Val66Met polymorphism, within the human BDNF gene, causes impaired activity-dependent secretion of neuronal BDNF and impairments to some forms of memory. We evaluated whether sex and BDNF genotype (Val66Met polymorphism (Met/Met) versus wild-type (Val/Val)) influenced the ability of voluntary running to enhance cognition and hippocampal neurogenesis in mice. Middle-aged C57BL/6J (13 months) mice were randomly assigned to either a control or an aerobic training (AT) group (running disk access). Mice were trained on the visual discrimination and reversal paradigm in a touchscreen-based technology to evaluate cognitive flexibility. BDNF Met/Met mice had fewer correct responses compared to BDNF Val/Val mice on both cognitive tasks. Female BDNF Val/Val mice showed greater cognitive flexibility compared to male mice regardless of AT. Despite running less than BDNF Val/Val mice, AT improved performance in both cognitive tasks in BDNF Met/Met mice. AT increased neurogenesis in the ventral hippocampus of BDNF Val/Val mice of both sexes and increased the proportion of mature type 3 doublecortin-expressing cells in the dorsal hippocampus of female mice only. Our results indicate AT improved cognitive performance in BDNF Met/Met mice and increased hippocampal neurogenesis in BDNF Val/Val mice in middle age. Furthermore, middle-aged female mice may benefit more from AT than males in terms of neuroplasticity, an effect that was influenced by the BDNF Val66Met polymorphism.

Brain Derived Neurotrophic Factor Deficiency is Associated with Cognitive Impairment and Elevated Phospholipase A2 Activity in Plasma of Mice

Decreased levels of Brain-Derived Neurotrophic Factor (BDNF) are a common finding in schizophrenia. Another well-documented protein linked to schizophrenia is intracellular Ca2+-independent Phospholipase (PLA2). However, the potential association between PLA2 and BDNF with regard to schizophrenia has yet to be examined.In the present study, male and female BDNF knockout mice, a possible genetic model of schizophrenia, were exposed to prenatal stress and tested in the nest test, open field test and T-maze. Following behavioral tests, whole brain and plasma samples were harvested to measure the activity of PLA2. BDNF knockout mice showed cognitive deficits in the T-maze. Furthermore, there was a quadratic association of PLA2 with performance in the open field test. Moreover, BDNF deficiency and female sex were associated with elevated plasma PLA2 levels. The cognitive impairment of BDNF heterozygous mice as well as their increased PLA2 activity in plasma is consistent with findings in schizophrenia patients. The particular elevation of PLA2 activity in females may partly explain sex differences of clinical symptoms in schizophrenia (e.g. age of onset, severity of symptoms). Additionally, PLA2 was significantly correlated with body and adrenal weight after weaning, whereby the latter emphasizes the possible connection of PLA2 with steroidogenesis.

Treadmill exercise sex-dependently alters susceptibility to depression-like behaviour, cytokines and BDNF in the hippocampus and prefrontal cortex of rats with sporadic Alzheimer-like disease

Alzheimer's disease (AD) is associated with increased depression-related behaviours. Previous studies have reported a greater risk of AD and depression in women. In recent years, we and others have provided evidence that exercise during life could be used as a therapeutic strategy for stress-related disorders such as depression. The main goal of the current study was to determine whether treadmill exercise during life can reduce depression-related behaviours in male and female Wistar rats with sporadic Alzheimer-like disease (ALD). Animals were subjected to treadmill exercise eight weeks before and four weeks after ALD induction by streptozocin (STZ). We measured body weight, food intake, and depression-related symptoms in rats using five behavioural tests. We measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the hippocampus and prefrontal cortex of animals. Our findings showed that exercise but not ALD induction decreased body weight and food intake in male and female rats. ALD induction increased depression-related symptoms and hippocampal TNF-α in male and female rats. Besides, treadmill exercise alone decreased depression-related behaviours and increased hippocampal BDNF in females but not males. We also found that treadmill exercise decreased depression-related behaviours and TNF-α in the hippocampus and prefrontal cortex, and increased IL-10 in the prefrontal cortex and BDNF in the hippocampus of female ALD-induced rats. However, treadmill exercise only reduced anhedonia-like behaviour and hippocampal TNF-α in male ALD-induced rats. Overall, the evidence from this study suggests that treadmill exercise alters depression-related behaviours, brain BDNF and cytokines in a sex-dependant manner in rats with sporadic Alzheimer-like disease.

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex

Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/−) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/− mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/−. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/− again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/− remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/− mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.

Brain-derived neurotrophic factor (BDNF) determines a sex difference in cue-conditioned alcohol seeking in rats

Alcohol use disorder is a detrimental addictive disease that develops through prolonged ethanol exposure and regular intoxication. However, the changes in the underlying neurobiology leading to alcohol addiction remain unclear. Brain-Derived Neurotrophic Factor (BDNF) is implicated in substance abuse disorders including alcoholism. As the vast majority of previous animal model studies have concentrated on males only, the aim of this study was to determine whether endogenous BDNF mediates alcohol seeking in a sex-specific manner.We used an operant self-administration paradigm where the animals were trained in operant chambers to self-administer a 10% ethanol solution, and compared male and female BDNF heterozygous (HET) and wildtype (WT) rats. Over several weeks, the animals progressed through acquisition, progressive ratio, extinction, and reinstatement phases.There were no significant sex or genotype differences in the number of alcohol-paired lever presses during acquisition, progressive ratio and extinction. However, a significant difference between male and female WT rats following alcohol-primed reinstatement was completely absent in BDNF HET rats suggesting a role of BDNF in sex differences in alcohol seeking after abstinence. Female BDNF HET rats showed significantly higher number of alcohol-paired lever presses during reinstatement than female WT controls.These findings suggest that BDNF regulatory pathways are involved in sex differences in reinstatement of alcohol intake and emphasize the need to include both male and female animals to explore sex-specific interactions in addiction neurocircuitry.

The effects of adolescent methylphenidate exposure on the behavioral and brain-derived neurotrophic factor response to nicotine.

This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain-derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a "school day" regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45-P63 and tested after a three-day drug washout on the forced swim stress task on P67-P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44-P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre-exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent.

Hypothalamic–pituitary–adrenal axis hyperactivity is associated with decreased brain-derived neurotrophic factor in female suicide attempters

Introduction: Both decreased levels of brain-derived neurotrophic factor (BDNF) and hypothalamic–pituitary–adrenal (HPA) axis dysregulation may be involved in the pathophysiology of suicidal behaviour, as well as cognitive symptoms of depression. Pre-clinical and clinical studies have shown interactions between HPA-axis activity and BDNF, but this has not been studied in a clinical cohort of suicidal subjects. The purpose of this study was, therefore, to investigate associations between HPA-axis activity and BDNF in suicide attempters. Furthermore, this study examined the relationship between the HPA-axis, BDNF, and cognitive symptoms in suicidal patients. Since previous data indicate gender-related differences in BDNF and the HPA axis, males and females were examined separately.Method: Seventy-five recent suicide attempters (n = 41 females; n = 34 males) were enrolled in the study. The Dexamethasone Suppression Test (DST) was performed and BDNF in plasma were analysed. Patients were evaluated with the Comprehensive Psychopathological Rating Scale (CPRS) from which items ‘Concentration difficulties’ and ‘Failing memory’ were extracted.Results: Only among females, DST non-suppressors had significantly lower BDNF compared to DST suppressors (p = 0.022), and there was a significant correlation between post-DST serum cortisol at 8 a.m. and BDNF (rs = −0.437, p = 0.003). Concentration difficulties correlated significantly with post-DST cortisol in all patients (rs = 0.256, p = 0.035), in females (rs = 0.396, p = 0.015), and with BDNF in females (rs = −0.372, p = 0.020).Conclusion: The findings suggest an inverse relationship between the HPA-axis and BDNF in female suicide attempters. Moreover, concentration difficulties may be associated with low BDNF and DST non-suppression in female suicide attempters.

Serum brain-derived neurotrophic factor (BDNF) is not regulated by testosterone in transmen.

Brain morphology significantly differs between the sexes. It has been shown before that some of these differences are attributable to the sex-specific hormonal milieu. Brain-derived neurotrophic factor (BDNF) is involved in myriads of neuroplastic processes and shows a sexual dimorphism. Transsexual persons may serve as a model to study sex steroid-mediated effects on brain plasticity. We have recently demonstrated that serum levels of BDNF are reduced in transwomen following 12 months of cross-sex hormone treatment. We now wanted to look at the effects of testosterone treatment on BDNF in transmen. In contrast to our initial hypothesis, BDNF levels did not significantly change, despite dramatic changes in the sex-hormonal milieu. Our data indicate that testosterone does not seem to play a major role in the regulation of BDNF in females.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-015-0055-5) contains supplementary material, which is available to authorized users.

Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism.

Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects with different ADs subtypes such as Social and Specific Phobias (PHSOC, PHSP), Generalized Anxiety Disorder (GAD), and Panic Disorder (PAD). Analysis of the population as a whole or individual village showed no significant correlation between serum BDNF levels and Val66Met polymorphism and no association with anxiety levels. Stratification of subjects highlighted a significant decrease in serum BDNF in females with GAD and males with PHSP. This study indicates low heritability and absence of any impact of the Val66Met polymorphism on circulating concentrations of BDNF. Our results show that BDNF is not a general biomarker of anxiety but serum BDNF levels correlate in a gender-specific manner with ADs subtypes.

Potentiated Striatal Dopamine Release Leads to Hyperdopaminergia in Female Brain-Derived Neurotrophic Factor Heterozygous Mice

The goal of this study was to determine whether a reduction in brain-derived neurotrophic factor (BDNF) levels in female mice leads to dopaminergic system dysregulation. Through a series of in vivo brain microdialysis and slice voltammetry experiments, we discerned that female BDNF heterozygous (BDNF(+/-)) mice are hyperdopaminergic, similar to their male BDNF(+/-) counterparts. Zero-net flux microdialysis results showed that female BDNF(+/-) mice had increased striatal extracellular dopamine levels, while stimulated regional release by high potassium concentrations potentiated dopamine release through vesicular-mediated depolarization. Using the complementary technique of fast scan cyclic voltammetry, electrical stimulation evoked greater dopamine release in the female BDNF(+/-) mice, whereas dopamine uptake remained unchanged relative to that of female wildtype mice. Following psychostimulant methamphetamine administration, female BDNF(+/-) mice showed potentiated dopamine release compared to their wildtype counterparts. Taken together, these dopamine release impairments in female mice appear to result in a hyperdopaminergic phenotype without concomitant alterations in dopamine uptake.

Sex-specific and region-specific changes in BDNF–TrkB signalling in the hippocampus of 5-HT1A receptor and BDNF single and double mutant mice

Brain-derived neurotrophic factor (BDNF) and serotonin 5-HT1A receptors are implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs. Here, we explore possible reciprocal interactions of 5-HT1A receptor knockout and the expression of BDNF, its receptor TrkB and downstream mitogen-activated protein kinase (MAPK) in the ventral (VHP) and dorsal hippocampus (DHP). We compared female and male double mutant mice (5-HT1A−/−/BDNF+/−) with single mutant mice (5-HT1A−/−, BDNF+/−) and wildtype (WT) controls. Protein expression of BDNF, TrkB, phosphorylation of TrkB (pTrkB) and MAPKs (ERK1, ERK2) was examined using Western blot analysis (n=5–7). As expected, the BDNF+/− mice showed ~50% BDNF reduction. Loss of 5-HT1A receptors induced a significant decrease in BDNF levels in the VHP in female mice. The pTrkB/TrkB ratio was also significantly decreased in female 5-HT1A−/− mice and 5-HT1A−/−/BDNF+/− mice but not in males. Despite markedly reduced BDNF levels in BDNF+/− mice and double mutants, ERK1 activation was unchanged in the female mice. In contrast, ERK2 activation was significantly elevated in the VHP of female BDNF+/− mice and double mutants. Given the greater vulnerability of women to develop depression and the role of the VHP in stress responses and anxiety-related behaviours, our results may shed more light on sex differences in depression and other psychiatric disorders with BDNF and 5-HT1A receptor dysfunction.

Long-term behavioral and NMDA receptor effects of young-adult corticosterone treatment in BDNF heterozygous mice

Psychiatric illnesses, such as schizophrenia, are most likely caused by an interaction between genetic predisposition and environmental factors, including stress during development. The neurotrophin, brain-derived neurotrophic factor (BDNF) has been implicated in this illness as BDNF levels are decreased in the brain of patients with schizophrenia. The aim of the present study was to assess the combined effect of reduced BDNF levels and postnatal stress, simulated by chronic young-adult treatment with the stress hormone, corticosterone. From 6weeks of age, female and male BDNF heterozygous mice and their wild-type controls were chronically treated with corticosterone in their drinking water for 3weeks. At 11weeks of age, male, but not female BDNF heterozygous mice treated with corticosterone exhibited a profound memory deficit in the Y-maze. There were no differences between the groups in baseline prepulse inhibition (PPI), a measure of sensorimotor gating, or its disruption by treatment with MK-801. However, an increase in startle caused by MK-801 treatment was absent in male, but not female BDNF heterozygous mice, irrespective of corticosterone treatment. Analysis of protein levels of the NMDA receptor subunits NR1, NR2A, NR2B and NR2C, showed a marked increase of NR2B levels in the dorsal hippocampus of male BDNF heterozygous mice treated with corticosterone. In the ventral hippocampus, significantly reduced levels of NR2A, NR2B and NR2C were observed in male BDNF heterozygous mice. The NMDA receptor effects in hippocampal sub-regions could be related to the spatial memory deficits and the loss of the effect of MK-801 on startle in these mice, respectively. No significant changes in NMDA receptor subunit levels were observed in any of the female groups. Similarly, no significant changes in levels of BDNF or its receptor, TrkB, were found other than the expected reduced levels of BDNF in heterozygous mice. In conclusion, the data show differential interactive effects of reduced levels of BDNF expression and corticosterone treatment on spatial memory and startle in male and female mice, accompanied by significant, but region-specific changes in NMDA receptor subunit levels in the dorsal and ventral hippocampus. These results could be important for our understanding of the interaction of neurodevelopmental stress and BDNF deficiency in cognitive and anxiety-related symptoms of psychiatric illnesses, such as schizophrenia.

P.1.027 Modulation of the neurotrophin brain-derived neurotrophic factor in serotonin transporter mutant rats

Decreased levels of Brain-Derived Neurotrophic Factor (BDNF) are a common finding in schizophrenia. Another well-documented protein linked to schizophrenia is intracellular Ca2+-independent Phospholipase (PLA2). However, the potential association between PLA2 and BDNF with regard to schizophrenia has yet to be examined.In the present study, male and female BDNF knockout mice, a possible genetic model of schizophrenia, were exposed to prenatal stress and tested in the nest test, open field test and T-maze. Following behavioral tests, whole brain and plasma samples were harvested to measure the activity of PLA2. BDNF knockout mice showed cognitive deficits in the T-maze. Furthermore, there was a quadratic association of PLA2 with performance in the open field test. Moreover, BDNF deficiency and female sex were associated with elevated plasma PLA2 levels. The cognitive impairment of BDNF heterozygous mice as well as their increased PLA2 activity in plasma is consistent with findings in schizophrenia patients. The particular elevation of PLA2 activity in females may partly explain sex differences of clinical symptoms in schizophrenia (e.g. age of onset, severity of symptoms). Additionally, PLA2 was significantly correlated with body and adrenal weight after weaning, whereby the latter emphasizes the possible connection of PLA2 with steroidogenesis.

Sex-dependent and region-specific changes in TrkB signaling in BDNF heterozygous mice

Altered expression of neurotrophins may contribute to the pathogenesis of schizophrenia. Several studies suggest sex steroid hormones may be involved in the regulation of brain-derived neurotrophic factor (BDNF) signaling, as well as the symptoms of schizophrenia. This study aimed to identify sex differences in BDNF–TrkB signaling in the forebrain of wild type (WT) and BDNF heterozygous (+/−) mice. Protein expression of neurotrophins and TrkB were measured by Western blot analysis in brain regions pertinent to schizophrenia, namely the frontal cortex, striatum, and dorsal (DHP) and ventral hippocampus (VHP).In both the frontal cortex and striatum, protein expression levels of phosphorylated TrkB (pTrkB) over total TrkB (pTrkB/TrkB) was significantly increased in male, but not female BDNF+/− mice, suggesting sex-specific changes in TrkB signaling. pTrkB/TrkB levels were also elevated in the DHP of both male and female BDNF+/−, while levels remained unchanged in the VHP, indicating region-specific changes in TrkB signaling. Sex-specific phosphorylation of TrkB corresponded with downstream changes in ERK2 phosphorylation in the frontal cortex and striatum. No sex-specific effects of genotype were found in the expression of TrkB ligands, BDNF and NT-4. However, a marked, region-specific increase in NT-4 expression was found in the striatum of both male and female BDNF+/− mice.In conclusion, there are complex sex- and region-specific changes in BDNF–TrkB signaling in BDNF+/− mice. These results provide new insight into sex-dependent BDNF signaling in forebrain regions and assist in understanding the role of neurotrophins in schizophrenia.

The Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism modulates the effects of serious life events on impulsive aggression in patients with Borderline Personality Disorder

Introduction: A recent study reported the frequency of violent suicide attempts being higher in subjects reporting severe sexual abuse and carrying the BDNF Val/Val genotype. This finding might be of particular importance for studies in patients with Borderline Personality Disorder (BPD), because up to 71 percent of BPD patients report the experience of severe childhood trauma and „self-injury/suicide attempts“ is an important diagnostic criterion for BPD. Methods: 159 BPD patients were included in the study. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI), SLEs by the PTSD-section included in the Munich-Composite International Diagnostic Interview (M-CIDI). We analyzed 1) modulating effects of the BDNF Val66Met polymorphism on the effects of SLEs on impulsive aggression, and 2) modulating effects of the BDNF Val66Met polymorphism on the association between SLEs and impulsive aggression in the subgroup of female BPD patients. Results/Discussion: Childhood sexual abuse explained a 28.6% increment in variance account of BDHI sum score in BDNF Val/Val carriers, as well as a 32.5% increment in variance account in female BDNF Val/Val carriers. The study analyzing a specific gene x environment interaction in BPD patients suggests an interaction between SLEs and the BDNF Val66Met polymorphism in the regulation of impulsive aggression in BPD patients, specifically in females.