BDNF/TrkB: a possible therapeutic target for schizophrenia

BDNF/TrkB：精神分裂症的可能治疗靶点

基本信息

批准号：
8005040
负责人：
Anilkumar Pillai
金额：
$ 7.35万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8005040
关键词：
Address Adverse effects Adverse reactions Affinity Aminobutyric Acids Animals Antipsychotic Agents Attenuated Behavioral Brain Brain region Brain-Derived Neurotrophic Factor Cerebellum Chemicals Clinical Cognition Cognitive deficits Conduct Clinical Trials Corpus striatum structure Cysteamine Cysteine Cystinosis Development Dopamine Receptor Employee Strikes Functional disorder GABA Receptor GAD65 enzyme Genes Goals Haloperidol Hippocampus (Brain)Immunohistochemistry Impaired cognition Impairment Ligands Mediating Metabolic Minor Modality Molecular Target Motor Mus Neurobehavioral Manifestations Neuronal Plasticity Neurons Neurotransmitters Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Play Prefrontal Cortex Process Psychotic Disorders Reeler Mouse Regulation Research Role Schizophrenia Series Short-Term Memory Signal Transduction Specificity Supporting Cell Symptoms System Techniques Testing Therapeutic Vertebral column Western Blotting Wild Type Mouse Work aminothiol arm base cognitive function density drug development frontal lobe gamma-Aminobutyric Acid improved information processing interest mRNA Expression neuronal growth neurotransmission novel prepulse inhibition prevent protein expression public health relevance repaired research clinical testing research study sensory gating serotonin receptor therapeutic target translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): While cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, currently available antipsychotic drugs appear to have relatively minor effects on cognition. Our long-term goal is to develop better therapeutic modalities that target the known pathophysiology of schizophrenia. BDNF is a known regulator of GABA system and both BDNF and GABA systems have been shown to be disrupted in schizophrenia. Thus, enhancing BDNF signaling may offer the potential to ameliorate GABA deficits in schizophrenia. Our recent studies demonstrate that Cysteamine (an aminothiol degradation product of cysteine used clinically for the treatment of cystinosis) prevents haloperidol-induced reduction in BDNF/TrkB signaling in mouse prefrontal cortex (PFC), and it also increases GAD67 protein expression through TrkB signaling in cortical neurons. While these preliminary observations are interesting, more experiments are necessary to understand whether the changes induced by Cysteamine on GABA system are functional. To this end, we propose the following experiments using heterozygous reeler mice, which have decreased GAD67 expression and TrkB signaling, in addition to many behavioral and neuroanatomical abnormalities homologous to schizophrenia. First, we will test the hypothesis that TrkB is expressed on GAD67-positive neurons in heterozygous reeler mice. We will determine the colocalization of TrkB and GAD67 in PFC, hippocampus, striatum and cerebellum. We will also determine the association of GAD67 with TrkB and BDNF in the above brain regions. Second, we will test the hypothesis that Cysteamine treatment enhances GAD67 expression and improves cognitive function in heterozygous reeler mice. We will determine the effect of Cysteamine treatment on PPI (pre-attentive processing) and Y-maze spontaneous alternation and novel arm tasks (spatial working and short term memory) in heterozygous and wild-type (WT) mice. We will also determine the effects of Cysteamine treatment on mRNA and protein expression of reelin, BDNF, TrkB and GABA synthesizing enzymes (GAD65 and GAD67) in PFC, hippocampus, striatum and cerebellum of heterozygous and WT mice after cognitive function tests. It is our hope that Cysteamine by improving BDNF signaling (and, as a result, GABA function) will improve cognitive deficits that are commonly observed in schizophrenia. The results from this exploratory study (R03) will serve as a proof of concept for the development a novel (pathophysiology- based) therapeutic approach for schizophrenia. PUBLIC HEALTH RELEVANCE: This application will explore the role of brain derived neurotrophic factor (a key brain chemical supporting cell development/repair)-mediated pathway as a treatment strategy for schizophrenia.

描述（由申请人提供）：虽然认知功能障碍被认为是精神分裂症更令人衰弱的症状之一，但目前可用的抗精神病药对认知的影响似乎相对较小。我们的长期目标是开发针对精神分裂症的已知病理生理学的更好的治疗方法。 BDNF是GABA系统的已知调节剂，BDNF和GABA系统都被证明在精神分裂症中被破坏。因此，增强BDNF信号传导可能会为精神分裂症中的GABA缺陷提供潜力。我们最近的研究表明，甲氨酸（半胱氨酸的氨基硫醇降解产物用于临床治疗囊肿性治疗）可防止卤吡啶酚诱导的小鼠前额叶皮层（PFC）中BDNF/TRKB信号的降低，并且还通过TrkBB中的GAD67蛋白质表达了CALBB信号。尽管这些初步观察很有趣，但需要更多的实验才能了解Cysteamine在GABA系统上引起的变化是否功能。为此，除了许多行为和神经解剖异常异常外，我们还建议使用杂合卷轴小鼠进行以下实验，这些实验降低了GAD67表达和TRKB信号传导。首先，我们将检验以下假设：TRKB在杂合卷轴小鼠中的GAD67阳性神经元上表达。我们将在PFC，海马，纹状体和小脑中确定TRKB和GAD67的共定位。我们还将确定上述大脑区域中GAD67与TRKB和BDNF的关联。其次，我们将测试cysteamine治疗增强GAD67表达并改善杂合子卷轴小鼠的认知功能的假设。我们将确定Cysteamine治疗对杂合和野生型（WT）小鼠中PPI（召集前处理）和Y迷宫的自发交替（空间工作和短期记忆）的影响。我们还将确定西星治疗对Reelin，BDNF，TRKB和GABA合成酶（GAD65和GAD67）在PFC，Hippocampus，Hippocampus，Striatum和Cerebellum的蛋白质和蛋白质表达后的影响。我们希望Cysteamine通过改善BDNF信号传导（因此，GABA功能）将改善精神分裂症中通常观察到的认知缺陷。这项探索性研究的结果（R03）将作为发展（基于病理生理学的）精神分裂症的新型治疗方法的概念证明。公共卫生相关性：该应用将探讨脑衍生的神经营养因子（一种支持细胞开发/修复的关键大脑化学因素）作为精神分裂症的治疗策略。