BDNF/TrkB: a possible therapeutic target 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虚弱的症状之一，但目前可用的抗精神病药物对认知的影响似乎相对较小。我们的长期目标是开发针对已知的精神分裂症病理生理学的更好的治疗方式。BDNF是已知的GABA系统的调节因子，BDNF和GABA系统在精神分裂症中都被证明是被破坏的。因此，增强BDNF信号可能提供了改善精神分裂症患者GABA缺陷的可能性。我们最近的研究表明，半胱胺(临床上用于治疗胱氨酸病的半胱氨酸的氨基硫醇降解产物)可以阻止氟哌啶醇诱导的小鼠前额叶皮质BDNF/TrkB信号的减少，并通过TrkB信号增加皮质神经元GAD67蛋白的表达。虽然这些初步观察是有趣的，但还需要更多的实验来了解半胱胺对GABA系统的影响是否起作用。为此，我们建议使用杂合子Reeler小鼠进行以下实验，这些实验降低了GAD67的表达和TrkB信号，以及许多与精神分裂症相关的行为和神经解剖学异常。首先，我们将检验TrkB在杂合子Reeler小鼠的GAD67阳性神经元上表达的假设。我们将确定TrkB和GAD67在前额叶、海马体、纹状体和小脑中的共存。我们还将确定GAD67与上述脑区TrkB和BDNF的关联。其次，我们将验证半胱胺治疗增强GAD67表达并改善杂合子Reeler小鼠认知功能的假设。我们将确定半胱胺治疗对杂合子和野生型(WT)小鼠的PPI(前注意加工)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测定半胱胺处理对杂合子和WT小鼠PFC、海马、纹状体和小脑中Reelin、BDNF、TrkB和GABA合成酶(GAD65和GAD67)的mRNA和蛋白表达的影响。我们希望半胱胺通过改善BDNF信号(从而改善GABA功能)来改善通常在精神分裂症中观察到的认知缺陷。这项探索性研究(R03)的结果将作为开发一种新的(基于病理生理学的)精神分裂症治疗方法的概念证明。 公共卫生相关性：这项应用将探索脑源性神经营养因子(一种支持细胞发育/修复的关键大脑化学物质)介导的途径作为精神分裂症治疗策略的作用。

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.