Reduced maternal and cord nerve growth factor levels in preterm deliveries

Nerve growth factor (NGF) is a neurotrophin, which exerts an important role in the development and function of the central and peripheral nervous system. There is limited information regarding the levels of NGF during pregnancy and its role in fetal development. We have earlier reported increased oxidative stress in pregnancy complications. The present study examines the levels of NGF in maternal and cord samples in preterm deliveries and its association with oxidative stress marker. A total number of 96 women delivering preterm (<37 weeks gestation) and 94 women delivering at term (control group) (≥37 weeks gestation) were recruited. Plasma NGF levels were measured in both mother and cord plasma using the Emax Immuno Assay System Promega kit. Maternal and cord plasma NGF levels were significantly reduced (p<0.05 for both) in women delivering preterm as compared to term. There was a positive association between maternal and cord plasma NGF levels (p=0.022). Maternal NGF levels were negatively (p=0.017) associated with maternal malondialdehyde (MDA) levels. Reduced cord NGF levels may affect fetal growth in preterm deliveries which may have implications for the neurodevelopmental pathologies in later life. Circulating maternal NGF levels in preterm pregnancies may be a useful marker to predict NGF levels in the neonate.     

Effects of fluoxetine and venlafaxine on serum brain derived neurotrophic factor levels in depressed patients

Background

Several studies demonstrated that depressed patients had low serum BDNF levels which correlated with the severity of their depression, and antidepressant treatment increases levels of serum BDNF in depressed patients. It was speculated that agents acting on both noradrenergic and serotonergic transporters might have a greater influence on BDNF levels. The aim of our study was to determine effects of venlafaxine vs. fluoxetine on serum BDNF levels in depressive patients.

Methods

Forty-three patients diagnosed as major depressive disorder according to DSM-IV are included in the study. Forty-three patients were randomized to take fluoxetine (22 cases) or venlafaxine (21 cases). Serum levels of BDNF were measured by ELISA at baseline and 6 weeks after the start of treatment.

Results

Baseline levels of BDNF were not significantly different between the patient group and the controls. But male patients and the male controls showed statistical differences with respect to baseline BDNF levels. BDNF levels of the patient group did not change with treatment. Yet, the increase of BDNF levels was close to statistically significant in the fluoxetine group, whereas not significant in the venlafaxine group. There were no significant differences in baseline and 6th week BDNF levels between the responders and the non-responders.

Conclusion

Further studies controlling for a wide variety of confounding variables are needed, which may help to reach a clear conclusion about the potential of BDNF as a biomarker for depression or as a predictor of antidepressant efficacy.     

The influence of aging on the methylation status of brain‐derived neurotrophic factor gene in blood

Objective

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.

Methods

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.

Results

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.

Conclusion

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.     

广泛性焦虑障碍治疗前后血清脑源性神经营养因子水平的变化

目的研究广泛性焦虑障碍(generalized anxiety disorder,GAD)患者血清脑源性神经营养因子(brain derived neurotrophic factor,BDNF)水平的特点及其治疗变化。方法收集GAD患者及正常对照者各40名,采用帕罗西汀片有效治疗量治疗12周,治疗前后采用汉密尔顿焦虑量表(Hamilton Anxiety Scale,HAMA)进行疗效评估,采用ELISA法测定血清BDNF的浓度并与对照组比较。结果治疗前GAD患者的血清BDNF水平[(26.03±10.52)ng/mL]低于对照组[(43.27±10.28)ng/mL],治疗后GAD患者血清BDNF水平[(35.85±11.96)ng/mL]较治疗前升高,但仍低于正常对照组,其差异均有统计学意义(P均<0.05);治疗后GAD显效患者[(39.43±12.35)ng/mL]与对照组血清BDNF水平的差异无统计学意义(P>0.05);基线时,GAD患者血清BDNF水平与HAMA量表总分、精神性焦虑因子分呈负相关(P<0.05),与躯体性焦虑因子分的相关没有统计学意义(P>0.05);治疗后,GAD患者血清BDNF水平的变化与HAMA总分、躯体性焦虑因子分、精神性焦虑因子分变化均呈负相关(P均<0.05)。结论血清BDNF水平可能是GAD的状态性指标之一。     

Deafferentation-associated changes in afferent and efferent processes in the guinea pig cochlea and afferent regeneration with chronic intrascalar brain-derived neurotrophic factor and acidic fibroblast growth factor

Deafferentation of the auditory nerve from loss of sensory cells is associated with degeneration of nerve fibers and spiral ganglion neurons (SGN). SGN survival following deafferentation can be enhanced by application of neurotrophic factors (NTF), and NTF can induce the regrowth of SGN peripheral processes. Cochlear prostheses could provide targets for regrowth of afferent peripheral processes, enhancing neural integration of the implant, decreasing stimulation thresholds, and increasing specificity of stimulation. The present study analyzed distribution of afferent and efferent nerve fibers following deafness in guinea pigs using specific markers (parvalbumin for afferents, synaptophysin for efferent fibers) and the effect of brain derived neurotrophic factor (BDNF) in combination with acidic fibroblast growth factor (aFGF). Immediate treatment following deafness was compared with 3-week-delayed NTF treatment. Histology of the cochlea with immunohistochemical techniques allowed quantitative analysis of neuron and axonal changes. Effects of NTF were assessed at the light and electron microscopic levels. Chronic BDNF/aFGF resulted in a significantly increased number of afferent peripheral processes in both immediate- and delayed-treatment groups. Outgrowth of afferent nerve fibers into the scala tympani were observed, and SGN densities were found to be higher than in normal hearing animals. These new SGN might have developed from endogenous progenitor/stem cells, recently reported in human and mouse cochlea, under these experimental conditions of deafferentation-induced stress and NTF treatment. NTF treatment provided no enhanced maintenance of efferent fibers, although some synaptophysin-positive fibers were detected at atypical sites, suggesting some sprouting of efferent fibers.     

Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve

Even after reconstructive surgery, major functional impairments remain in the majority of patients with peripheral nerve injuries. The application of novel emerging therapeutic strategies, such as lentiviral (LV) vectors, may help to stimulate peripheral nerve regeneration at a molecular level. In the experiments described here, we examined the effect of LV vector-mediated overexpression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on regeneration of the rat peripheral nerve in a transection/repair model in vivo. We showed that LV vectors can be used to locally elevate levels of NGF and GDNF in the injured rat peripheral nerve and this has profound and differential effects on regenerating sensory and motor neurons. For sensory neurons, increased levels of NGF and GDNF do not affect the number of regenerated neurons 1 cm distal to a lesion at 4 weeks post-lesion but do cause changes in the expression of markers for different populations of nociceptive neurons. These changes are accompanied by significant alterations in the recovery of nociceptive function. For motoneurons, overexpression of GDNF causes trapping of regenerating axons, impairing both long-distance axonal outgrowth and reinnervation of target muscles, whereas NGF has no effect on these parameters. These observations show the feasibility of combining surgical repair of the transected nerve with the application of viral vectors. Furthermore, they show a difference between the regenerative responses of motor and sensory neurons to locally increased levels of NGF and GDNF.     

中老年抑郁症患者执行功能障碍及其与血清脑源性神经营养因子的关系

目的探讨中老年抑郁症患者执行功能及其与血清脑源性神经营养因子(BDNF)的关系,为了解中老年抑郁症患者执行功能及生化指标的变化提供理论基础。方法选取2014年6月-2015年1月在贵州医科大学附属医院心理科住院的、符合《精神障碍诊断与统计手册(第4版)》(DSM-IV)抑郁症诊断标准的中老年住院患者78例(抑郁组),并于同期选取贵州医科大学附属医院职工、心理科患者家属80例(对照组),根据抑郁自评量表(SDS)评分将抑郁组分为轻中度抑郁组和重度抑郁组。采用执行功能行为评定量表成人版自评问卷(BRIEF-A)评定抑郁组和正常对照组的执行功能,包括行为管理指数(BRI)和元认知指数(MI)。采用生物素双抗体夹心酶联免疫吸附法(ELISA)测定BDNF水平。结果抑郁组BRIEF-A总评分、BRI、MI及各因子评分均高于正常对照组(P均0.01);重度抑郁组的抑制、转移、工作记忆因子评分与轻中度抑郁组差异无统计学意义(P均0.05),而BRIEF-A总评分及其他因子评分均高于轻中度抑郁组(P均0.05)。中老年抑郁组BDNF水平低于正常对照组,重度抑郁组BDNF水平低于轻中度抑郁组(P均0.05)。执行功能总评分及各因子评分与BDNF水平的相关均无统计学意义(P均0.05)。结论与正常中老年人相比,中老年抑郁症患者执行功能明显受损,中老年抑郁组患者BDNF水平较低,且随抑郁程度加重而下降。抑郁症患者的执行功能和BDNF水平无明显相关性。     

Effects of escitalopram on the regulation of brain‐derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress

Escitalopram (ES‐CIT) is a widely used, highly specific antidepressant. Until now there has been very little evidence on how this drug under pathological conditions affects an important feature within the pathophysiology of stress‐related disorders such as depression: the endogenous neurotrophins. By using a well‐characterized rat model in which chronic stress induces depressive‐like behavior, the levels of neurotrophins brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were determined in representative brain regions and serum using a highly sensitive improved fluorometric two‐site ELISA system. There was a significant increase of BDNF in the left and right cortices after stress treatment (twofold increase) that was reversed by application of ES‐CIT. An ES‐CIT‐dependent NGF reduction in stressed rats was detectable in the right cortex only (P = 0.027). The left hippocampus revealed significantly higher amounts of BDNF (2.5‐fold increase) protein than the right hippocampus. These interhemispheric differences were unrelated to stress or ES‐CIT treatment in all animals. BDNF and NGF of the frontal cortex, cerebellum, and serum did not change between the study groups. There was a negative correlation between body weight and serum BDNF, independent of stress or ES‐CIT treatment. In conclusion, BDNF and NGF show substantial changes in this rodent model of chronic social stress, which is susceptible to antidepressant treatment with ES‐CIT and therefore may constitute a neurobiological correlate for the disease. © 2009 Wiley‐Liss, Inc.     

Altered serum levels of vascular endothelial growth factor and glial-derived neurotrophic factor but not fibroblast growth factor-2 in treatment-naive children with attention deficit/hyperactivity disorder

Abstract

Background and aim: Recent evidence suggests that growth factors might be involved in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of this study was to determine whether serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) were altered in children with ADHD.

Methods: Serum levels of BDNF, GDNF, NT-3, NGF, VEGF and FGF-2 were analyzed in 49 treatment- naive children with ADHD and age, gender matched 36 healthy controls using enzyme-linked immunosorbent assay. ADHD symptoms were scored by Du Paul ADHD Rating Scale and Strengths and Difficulties Questionnaire.

Results: We found that serum VEGF levels were significantly lower (p?<?0.001) and GDNF levels were significantly higher in ADHD group compared to control group (p?=?0.003). However, we found no correlations between ADHD symptoms and serum VEGF or GDNF levels. Furthermore, we observed no significant alterations in serum BDNF, NT-3, NGF, FGF-2 levels in children with ADHD.

Conclusion: To our knowledge, the present study is the first to examine serum VEGF and FGF-2 levels in children with ADHD. Our results indicate that VEGF and GDNF might be involved in the etiology of ADHD. Further studies are required to determine the role of growth factors in the etiology and consequently in the treatment of ADHD.     

重复经颅磁刺激对首发精神分裂症患者血清脑源性神经营养因子的影响

目的分析高频重复经颅磁刺激(rTMS)对首发精神分裂症患者血清脑源性神经营养因子(BDNF)的影响。方法选取82例以阴性症状为主的首发精神分裂症患者,使用随机数表将82例患者分为对照组41例和观察组41例,2组均使用常规药物治疗,观察组同时予以真刺激治疗,对照组予以假刺激治疗,对比2组治疗结果。结果治疗4周后观察组PANSS(阳性和阴性症状量表)总分、阴性症状评分、一般病理评分及血清BDNF浓度均优于治疗前,且优于对照组(P0.05);对照组PANSS总分、阴性症状评分、阳性症状评分、一般病理评分及血清BDNF浓度与之前相比无明显变化(P0.05)。观察组BDNF浓度变化与PANSS总分及各因子的变化无明显相关性(P0.05)。结论rTMS可显著增加首发精神分裂症患者的血清BDNF水平,但血清BDNF水平变化与其临床症状的改善无明显相关性。     

Differential expression of human placental neurotrophic factors in preterm and term deliveries

Neurotrophic factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are involved in development of the placenta and fetal brain. A series of human and animal studies in our department have shown that micronutrients (folic acid, vitamin B₁₂) and omega 3 fatty acids like DHA are all interlinked in the one carbon cycle. Any alterations in one carbon components will lead to changes in methylation patterns that further affect the gene expression at critical periods of development resulting in complications during pregnancy. This may further contribute to risk for neurodevelopmental disorders in children born preterm. Therefore this study for the first time examines the mRNA levels from preterm and term placentae. A total number of 38 women delivering preterm (<37 weeks gestation) and 37 women delivering at term (=>37 weeks gestation) were recruited. The mRNA levels of BDNF and NGF were analyzed by real time quantitative polymerase chain reaction. Our results indicate that BDNF and NGF mRNA levels were lower in preterm group as compared to term group. There was a positive association of placental BDNF and NGF mRNA levels with cord plasma BDNF and NGF levels. The differential expression of BDNF and NGF gene in preterm placentae may also alter the vascular development in preterm deliveries. Our data suggests that the reduced mRNA levels of BDNF and NGF may possibly be a result of altered epigenetic mechanisms and may have an implication for altered fetal programming in children born preterm.     

CSF levels of a set of neurotrophic factors (brain-derived neurotrophic factor,nerve growth factor) and neuropeptides (neuropeptide Y,galanin) in epileptic children

This paper aims to investigate the possible roles of a set of neurotrophic factors (brain-derived neurotrophic factor-BDNF, nerve growth factor-NGF) and neuropeptides (neuropeptide Y-NPY, and galanin) in children with active epileptogenesis. The cerebrospinal fluid (CSF) levels of BDNF, NPY, NGF and galanin were measured with enzyme-linked immunosorbent assays in epileptic children (n = 73) and controls (n = 64). There were no significant alterations in the CSF levels of BDNF, NPY and NGF in epileptic children with active clinical seizures compared with the levels of controls. However profoundly depressed galanin levels were found in infants with epileptic encephalopathy (mean ± SD:0.63 ± 0.19 pg/ml) and significantly increased galanin levels were measured in children with drug resistant epilepsy during the period of status epilepticus (mean ± SD: 6.92 ± 1.19, pg/ml pg/ml) compared with the levels of controls. Depressed levels of galanin might reflect a defective anti-epileptogenic effect of galanin in infants with epileptic encephalopathy. On the contrary, increased CSF levels of galanin might be a result of anti-epileptogenic effects of this peptide in epileptic children with status epilepticus.     

Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay

Brain-derived neurotrophic factor (BDNF) is one of several endogenous proteins that play key roles in neuronal development and homeostasis. We describe here the characterization and use of a sensitive and specific enzyme-linked immunoassay (EIA) for BDNF protein. Recombinant BDNF was detected at concentrations as low as 10 pg/ml, whereas the EIA did not detect NT-3, NT-4/5, or NGF at concentrations as high as 100 ng/ml. Because BDNF protein sequences are identical among humans, mice, and rats, we utilized the BDNF EIA to detect BDNF in the circulation or brain regions of these species. High concentrations of BDNF were detected in human and rat serum, and up to 50-fold lower BDNF levels were present in citrated human or rat plasma. The BDNF signal (66–141 pg/ml) in 20% human plasma was completely blocked by pre-exposure of plasma to a monoclonal antibody (Mab) specific for BDNF but not by exposure to 5-fold greater concentrations of an irrelevant Mab of the same isotype (IgGl). There was a significant and positive correlation (r = +0.86) between plasma levels of BDNF and serotonin, an indoleamine that is specifically released from activated platelets. These results are consistent with the view that the BDNF detected in human and rat plasma is derived from platelet degranulation, and that circulating levels of BDNF are negligible. In contrast to human or rat serum, mouse serum contained no detectable BDNF. However, BDNF protein was readily detectable at 108–256 ng/g of tissue in hippocampus, frontal cortex, and neostriatum of mice and rats. Thus, the failure to detect BDNF in murine serum was not due to an assay defect but highlights a significant species difference in the tissue-specific expression of BDNF that may be of biological importance. The presence of BDNF protein in blood and brain regions at quantities which greatly exceed those described for NGF confirm the abundant distribution of this broadly-acting neurotrophic factor.     

脑源性神经营养因子启动子区甲基化与孤独症谱系障碍关系初探

目的通过比较孤独症谱系障碍(autism spectrum disorders,ASD)患者和正常对照脑源性神经营养因子(brain derived neurotrophic factor,BDNF)基因启动子Ⅰ区和Ⅳ区各CpG单元甲基化率,探讨ASD可能的发病机制。方法选取ASD患者12例及正常对照12名,利用飞行时间质谱法检测全血中BDNF基因启动子Ⅰ和Ⅳ区各CpG单元甲基化率,并分析其相关性距离、进化关系,比较两组各单元甲基化率。结果在BDNF启动子Ⅰ区和Ⅳ区分别检测到17个和8个CpG单元的甲基化率。ASD患者组BDNF启动子Ⅰ区中CpG单元4、7、10、35,以及BDNF启动子Ⅳ区CpG单元11.12、14相关性距离较近,聚类成比较小的分支。ASD患者BDNF启动子Ⅰ区CpG单元5.6甲基化率低于对照组(P0.05),Ⅳ区CpG单元3和15甲基化率高于对照组(P0.05)。结论 ASD患者BDNF启动子Ⅰ区CpG单元5.6和Ⅳ区CpG单元3和15甲基化率在ASD患者组和对照组差异显著,提示BDNF启动子甲基化可作为ASD潜在的生物标志物深入研究。     

亨廷顿蛋白相关蛋白1与脑源性神经营养因子的胞吞关系的机制研究

目的探讨亨廷顿蛋白相关蛋白1(HAP1)与脑源性神经营养因子(mBDNF)胞吞的相关性和可能的机制。方法神经营养因子(NGF)诱导分化PC 1 2细胞,将荧光质粒HAP1A-CFP和(或)mBDNF-ds-red转染进入细胞,培养4 8 h后在含有BDNF或p7 5NTR抗体的培养基中继续培养,激光共聚焦显微镜观察荧光的表达情况及其在细胞中的定位;利用小鼠皮层神经元(正常型和HAP1基因敲除型)在生物素标记mBDNF的培养基中孵育6 0 m in,激光共聚焦显微镜观察皮层神经元免疫荧光的效果。结果共转染HAP1A-CFP和mBDNF-ds-red质粒的细胞,2种荧光蛋白存在部分共定位3 4%。共转染的细胞在抗BDNF培养基孵育下,或者单转染HAP1A-CFP质粒的细胞在mBDNF-ds-red荧光蛋白+抗BD-NF/抗p7 5NTR培养基孵育下,2种荧光蛋白几乎没有共定位现象。单转染HAP1A-CFP质粒的细胞在mBDNF-ds-red荧光蛋白培养基孵育下,mBDNF与HAP1蛋白的共定位比例高达9 3%。正常新生小鼠皮层神经元内可见内吞的mBDNF免疫荧光,HAP1基因敲除小鼠的皮层神经元内未见。结论 mBDNF的胞吞必需HAP1的表达和参与。     

Decreased levels of brain-derived neurotrophic factor in the remitted state of unipolar depressive disorder

Hasselbalch BJ, Knorr U, Bennike B, Hasselbalch SG, Greisen Søndergaard MH, Vedel Kessing L. Decreased levels of brain‐derived neurotrophic factor in the remitted state of unipolar depressive disorder. Objective: Decreased levels of peripheral brain‐derived neurotrophic factor (BDNF) have been associated with depression. It is uncertain whether abnormally low levels of BDNF in blood are present beyond the depressive state and whether levels of BDNF are associated with the course of clinical illness. Method: Whole‐blood BDNF levels were measured in blood samples from patients with unipolar disorder in a sustained state of clinical remission and in a healthy control group. Participants were recruited via Danish registers, a method that benefits from the opportunity to obtain well‐matched community‐based samples as well as providing a high diagnostic validity of the patient sample. Results: A total of 85 patients and 50 controls were included in the study. In multiple linear regression analyses, including the covariates age, gender, 17‐item Hamilton Depression Rating Scale scores, body‐mass index, education, smoking and physical exercise, patients with unipolar depressive disorder had decreased levels of BDNF compared to healthy control individuals [B = ?7.4, 95% CI (?11.2, ?3.7), = 0.21 P < 0.001]. No association between course of clinical illness and BDNF levels was present. Conclusion: Whole‐blood BDNF levels seem to be decreased in patients remitted from unipolar depressive disorder, suggesting that neurotrophic changes may exist beyond the depressive state.     

精神分裂症脑源性神经营养因子和海马结构改变的关联

精神分裂症是一种严重精神病,以幻觉、思维及行为紊乱和社会功能退化为特征,患病率为1％,给个人、家庭及社会带来极大负担。精神分裂症的研究涉及遗传、神经生化、病理生理、影像学等多个领域,但其确切病因及病理机制目前仍不明确。脑影像学研究表明,精神分裂症患者存在大脑结构异常,主要表现为侧脑室扩大和脑体积减小。     

The effect of early maternal separation on brain derived neurotrophic factor and monoamine levels in adult heterozygous reeler mice

OBJECTIVE AND METHODS: The reeler heterozygous (HZ) mice have provided a model for studying the relationship between reelin (a protein of extracellular matrix) haploinsufficiency and the emergence of neuropsychiatric diseases. In a neurodevelopmental framework, the enduring consequences of early maternal separation (5 h/day during the first postnatal week, or handling controls, H) were studied in reeler HZ and wild type (WT) mice at adulthood. The modulatory effects of a chronic treatment with the atypical antipsychotic olanzapine (OLZ, 1.5 mg/kg for 40 days) were also investigated. RESULTS: Early maternal separation had long-term effects on brain plasticity, with a reduction of brain- and glial- derived neurotrophic factor (BDNF and GDNF) in several brain areas of mice, but such a consequence was less marked in the HZ genotype. On the other hand, treatment with OLZ did not affect at all the GDNF but led to an increase of BDNF levels in maternally separated (SEP) mice, an effect which was far more marked in the HZ genotype. Brain levels of serotonin (5-HT) were markedly increased, striatal dopamine (DA) was increased, whereas metabolites and turnover were decreased, in SEP mice of both genotypes. The spontaneous home-cage activity was generally lower in HZ than WT mice, and OLZ treatment contrasted this hypoactivity profile. Maternal separation also decreased the interest toward an unknown mouse proposed as a social stimulus, but only in WT mice. CONCLUSION: We investigated the interplay between genetic vulnerability (reelin haploinsufficiency), the outcome of early stressful experiences, and the efficacy of the antipsychotic drug therapy. The reeler HZ genotype exhibited a slightly lower sensitivity to the environmental insult as well as an enhanced response to the atypical antipsychotic treatment.