Expression of Ca²⁺-dependent activator protein for secretion 2 is increased in the brains of schizophrenic patients

Ca²⁺-dependent activator protein for secretion 2 (CADPS2), a secretory granule associate protein, mediates monoamine transmission and the release of neurotrophins including brain-derived neurotrophic factor (BDNF) which have been implicated in psychiatric disorders. Furthermore, the expression of CADPS2deltaExon3, a defective splice variant of CADPS2, has been reported to be associated with autism. Based on these observations, we examined whether expression levels of CADPS2 and CADPS2deltaExon3 are altered in psychiatric disorders. Quantitative polymerase chain reaction analysis was performed for postmortem frontal cortex tissues (BA6) from 15 individuals with schizophrenia, 15 with bipolar disorder, 15 with major depression, and 15 controls (Stanley neuropathology consortium). The mean CADPS2 expression levels normalized to human glyceraldehyde-3phosphate dehydrogenase (GAPDH) or TATA-box binding protein levels was found to be significantly increased in the brains of the schizophrenia group, compared to the control group. On the other hand, the ratio of CADPS2deltaExon3 to total CADPS2 was similar in the 4 diagnostic groups. We then analyzed CADPS2 expression in blood samples from 121 patients with schizophrenia and 318 healthy controls; however, there was no significant difference between the two groups. Chronic risperidone treatment did not alter the expression of CADPS2 in frontal cortex of mice. The observed increase in the expression of CADPS2 may be related to the impaired synaptic function in schizophrenia.     

Melatonin improves 3-nitropropionic acid induced behavioral alterations and neurotrophic factors levels

Objective

This study sought to determine whether melatonin causes changes in neurotrophic factors and it protects against the mycotoxin 3-nitropropionic acid (3-NP) in brain tissue.

Methods

Rats were given 3-NP over four consecutive days (20 mg/kg BW), while melatonin was administered over 21 days (1 mg/kg/BW), starting after the last injection of 3-NP.

Results

Rats treated with 3-NP displayed significant changes in neurotrophic factor (BDNF and GDNF) levels, together with alterations in behavior; they also displayed extensive oxidative stress and a massive neuronal damage.

Conclusions

Melatonin improved behavioral alterations, reduced oxidative damage, lowered neurotrophic factor levels and neuronal loss in 3-NP-treated rats. These results suggest that melatonin exerts a neuroprotective action.     

A novel BDNF polymorphism affects plasma protein levels in interaction with early adversity in rhesus macaques

Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. In this report we describe the characterization of a single nucleotide polymorphism (SNP) in rhesus macaques, which results in a Val to Met transition in the pro-BDNF domain, similar to a well described variant in the human gene. Further, we tested the hypothesis that peripheral levels of BDNF, which is involved in the response to stress and in the pathophysiology of anxiety and depression, might be differentially affected in a non-human primate model of early adverse rearing in a genotype-dependent manner. Males and females rhesus macaques reared either with their mothers (MR), in peer-only groups (PR), or in a "surrogate/peer-reared" (SPR) condition with limited peer interactions, were used as experimental subjects. BDNF levels were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA procedure. Data indicate that BDNF levels were increased as a result of peer-rearing and that this increase was moderated by the presence of the SNP. Overall these data indicate that a SNP, which results in a Val to Met transition in the pro-BDNF domain, is present in rhesus macaques and is able to affect BDNF peripheral levels, thus making this primate model a fundamental tool to study gene by environment interactions involving the BDNF gene.     

Genetic influence on the working memory circuitry: behavior, structure, function and extensions to illness

Memantine is a partial NMDA receptor antagonist that has been shown to improve learning and memory in several animal models, and is approved for the treatment of Alzheimer's disease (AD). Chronic treatments using memantine in animal models of Alzheimer's disease show disease-modifying effects and suggest a potential neuroprotective function. The present study assessed the effects of both short- and long-term memantine treatment in a mouse model of Down syndrome (DS), the Ts65Dn mouse. The Ts65Dn mouse contains a partial trisomy of murine chromosome 16, and exhibits hippocampal-dependent memory deficits, as well as progressive degeneration of basal forebrain cholinergic neurons (BCFNs). Ts65Dn mice were treated with memantine for a period of 6 months, beginning at 4 months of age. At the end of treatment the mice underwent memory testing using novel object recognition and water radial arm maze tasks, and then histologically analyzed for markers of neurodegeneration. Memantine treatment improved spatial and recognition memory performance in the Ts65Dn mice, though not to the level of normosomic littermate controls. Despite these memory improvements, histological analysis found no morphological signs of neuroprotection of basal forebrain cholinergic or locus coeruleus neurons in memantine-treated Ts65Dn mice. However, memantine treatment of Ts65Dn mice gave rise to elevated brain-derived neurotrophic factor expression in the hippocampus and frontal cortex, suggesting a mechanism of behavioral modification. Thus, our findings provide further evidence for memory facilitation of memantine, but suggest pharmacological rather than neuroprotective effects of memantine both after acute and chronic treatment in this mouse model.     

不同配伍柴郁温胆汤对抑郁模型大鼠海马CREB和BDNF表达的影响

目的观察柴郁温胆汤及其不同配伍组合对抑郁模型大鼠海马环磷酸腺苷反应元件结合蛋白(CREB)和脑源性神经营养因子(BDNF)表达的影响。方法健康雄性SD大鼠70只,随机分为正常组、模型组、复方组、化痰组、调气血组、养心脾组和马普替林组。除正常组外,各组采用孤养加慢性轻度不可预见性刺激方法建立大鼠抑郁模型,从应激第2天起分别灌胃给药至实验第23天。采用免疫组化法检测大鼠海马CA3区CREB和BDNF的表达。结果与正常组相比,模型组大鼠海马CREB和BDNF表达的总面积、阳性细胞数和平均光密度均明显降低(P<0.01)。与模型组相比,复方组、化痰组、马普替林组能够显著上调大鼠海马CREB和BDNF表达(P<0.05或P<0.01);养心脾组能够提升CREB表达的总面积和阳性细胞数(P<0.05);调气血组能够提升BDNF表达的平均光密度(P<0.05)。结论柴郁温胆汤能够明显上调大鼠海马CREB和BDNF表达,其中以化痰药的配伍组合作用较明显。     

人参皂苷对慢性应激抑郁模型大鼠行为学及HPA轴、BDNF的影响

目的:探讨人参皂苷对慢性应激所致大鼠抑郁模型的干预作用.方法:通过测定大鼠血清中皮质酮(COR)、糖皮质激素受体(GR)、盐皮质激素受体(MR)和脑组织中神经营养(BDNF)的mRNA表达水平,探讨人参皂苷的抗抑郁机制.结果:与正常组大鼠比较,经过慢性应激6周后大鼠糖水偏好显著下降,强迫游泳测试不动时间明显增加,表明慢性应激导致大鼠产生抑郁样行为.同时,抑郁大鼠的血清COR水平增加,海马GR、海马及皮层BDNF的mRNA表达水平均明显降低.给予人参皂苷(12.5,25,50 mg·kg-1)6周后,发现其能显著改善由慢性应激所致的大鼠抑郁行为及生化指标.各个组间海马MR的mRNA表达水平没有显著差异.结论:人参皂苷的抗抑郁作用机制可能通过调节下丘脑-垂体-肾上腺轴功能,进而提高脑组织BDNF 表达水平.     

电针治疗抑郁模型大鼠快速起效海马区BDNF-TrkB机制研究

目的:探讨电针抗抑郁治疗快速起效的海马神经元保护和发生机制。方法:SD大鼠32只随机分为正常组、模型组、药物组(盐酸氟西汀)和电针组,每组8只。采用孤养和长期中等强度未预知应激制备应激大鼠抑郁症模型,运用免疫组化法观察治疗7天时各组大鼠在海马CA1、CA3、DG各区BDNF及TrkB阳性神经元的表达。结果:①抑郁症模型存在海马区BDNF、TrkB表达下降,表现为阳性神经元平均灰度值上升、目标总面积下降;②治疗第7天,电针组海马神经元的BDNF及受体TrkB平均灰度值下降,且显著低于药物组,尤以CA3区为甚(P<0.01);③治疗第7天,电针组海马神经元的BDNF及受体TrkB阳性神经元总面积均明显升高,且明显高于药物组,以在DG区较为显著(P<0.05)。结论:电针能提高抑郁模型大鼠海马锥体神经细胞的生存、促进神经元再生;电针抗抑郁快速起效与BDNF、TrkB表达的迅速增加有关。     

Enhancement of LTP in Aged Rats is Dependent on Endogenous BDNF

Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak θ-burst stimuli and dependent on co-activation of adenosine A_2A receptors (A_2AR), which are more expressed in aged rats. As θ-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak θ-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80-week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A_2AR antagonist, {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF.     

Lesion-induced synaptic plasticity in the somatosensory cortex of prenatally stressed rats

Prenatal stress exposure causes long-lasting impairments of the behavioral and neuroendocrine responses to later stressors of the offspring. Although mechanisms underlying these effects remain largely unknown, abnormalities in the neuronal plasticity might be responsible for neurobiological alterations. This study used the whisker-to-barrel pathway as a model system to investigate the effects of prenatal stress on lesion-induced plasticity of neurons. Pregnant rats were subjected to immobilization stress during the trigeminal neurogenesis period, corresponding to gestational days 12 to 17, for three hours a day. After birth, the middle row (C) whisker follicles of pups from the control and stressed groups were electrocauterized. Ten days later, tangentially sectioned cortical hemispheres were stained with cytochrome oxidase histochemistry to calculate the volumes of each barrel row (A-E) in both lesioned and intact sides of the cortex, using stereological methods. The adrenal to body weight ratios were significantly increased in stressed animals, when compared to the controls. The pattern and total volume of the barrel subfield remained unaltered, but the lesion-induced map plasticity index, calculated as the D/C ratio, decreased in stressed animals. In addition, the BDNF (Brain Derived Neurotrophic Factor), NT-3 (neurotrophin-3) and the cyclic AMP response element binding protein (CREB) phosphorylation levels in tissue homogenates of the barrel cortices were measured using the ELISA method. In prenatally stressed animals, the BDNF and NT-3 levels were reduced on the lesioned side, but significant CREB activation was observed on the intact side of the barrel cortex. Taken together, the results show that prenatal stress exposure negatively affects critical period plasticity by reducing the expansion of active barrels following peripheral whisker lesion. These changes arise independent of CREB phosphorylation and appear to be mediated by reduced levels of neurotrophins.     

High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies

High-dose corticosteroids have been reported to reduce symptoms of acute stress and post-traumatic stress in polytrauma patients and in animal studies. The underlying mechanism of action remains largely unclear. These issues were addressed in parallel in the clinical and preclinical studies below. In this preliminary study, 25 patients with acute stress symptoms were administered a single intravenous bolus of high-dose hydrocortisone (100–140 mg) or placebo within 6 h of a traumatic event in a prospective, randomized, double-blind, placebo-controlled pilot study. Early single high-dose hydrocortisone intervention attenuated the core symptoms of both the acute stress and of subsequent PTSD in patients. High-dose hydrocortisone treatment given in the first few hours after a traumatic experience was associated with significant favorable changes in the trajectory of exposure to trauma, as expressed by the reduced risk of the development of PTSD post-trauma. In parallel, a comparative study of morphological arborization in dentate gyrus and its modulating molecules was performed in stress-exposed animals treated with high-dose hydrocortisone. Steroid-treated stressed animals displayed significantly increased dendritic growth and spine density, with increased levels of brain-derived neurotrophic factor (BDNF) and obtunded postsynaptic density-95 (PSD-95) levels. The animal study provided insights into the potential mechanism of this intervention, as it identified relevant morphological and biochemical associations to the clinical observations. Thus, evidence from clinical and animal studies suggests that there is a “window of opportunity” in the early aftermath of trauma to help those who are vulnerable to the development of chronic PTSD.