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最令人衰弱的症状之一，但目前可用的抗精神病药物似乎对认知的影响相对较小。我们的长期目标是针对已知的精神分裂症病理生理学开发更好的治疗方式。 BDNF 是 GABA 系统的已知调节因子，BDNF 和 GABA 系统均已被证明在精神分裂症中受到破坏。因此，增强 BDNF 信号传导可能有可能改善精神分裂症中的 GABA 缺陷。我们最近的研究表明，半胱胺（半胱氨酸的氨基硫醇降解产物，临床上用于治疗胱氨酸病）可防止氟哌啶醇诱导的小鼠前额皮质 (PFC) 中 BDNF/TrkB 信号传导的减少，并且还可以通过 TrkB 信号传导增加 GAD67 蛋白的表达。皮质神经元。虽然这些初步观察结果很有趣，但还需要更多的实验来了解半胱胺对 GABA 系统引起的变化是否具有功能性。为此，我们提出使用杂合 reeler 小鼠进行以下实验，除了许多与精神分裂症同源的行为和神经解剖学异常外，这些小鼠还减少了 GAD67 表达和 TrkB 信号传导。首先，我们将测试 TrkB 在杂合 reeler 小鼠的 GAD67 阳性神经元上表达的假设。我们将确定 TrkB 和 GAD67 在 PFC、海马、纹状体和小脑中的共定位。我们还将确定上述大脑区域中 GAD67 与 TrkB 和 BDNF 的关联。其次，我们将检验半胱胺治疗增强杂合子 Reeler 小鼠中 GAD67 表达并改善认知功能的假设。我们将确定半胱胺治疗对杂合子和野生型 (WT) 小鼠的 PPI（前注意处理）和 Y 迷宫自发交替以及新的手臂任务（空间工作和短期记忆）的影响。我们还将在认知功能测试后确定半胱胺治疗对杂合子和WT小鼠PFC、海马、纹状体和小脑中reelin、BDNF、TrkB和GABA合成酶（GAD65和GAD67）mRNA和蛋白表达的影响。我们希望半胱胺通过改善 BDNF 信号传导（进而改善 GABA 功能）来改善精神分裂症中常见的认知缺陷。这项探索性研究 (R03) 的结果将作为开发一种新型（基于病理生理学）精神分裂症治疗方法的概念证明。公共健康相关性：本申请将探讨脑源性神经营养因子（支持细胞发育/修复的关键脑化学物质）介导的途径作为精神分裂症治疗策略的作用。