Therapeutic potential of GLS1 inhibition for the pharmacotherapy of schizophrenia

描述（由申请人提供）：调节异常的多巴胺能神经传递与精神分裂症的精神病理学密切相关。最近的研究强调了突触前谷氨酸传递减少的治疗前景。我们已经表明，从谷氨酸脱氢酶（GLS 1）基因敲除小鼠的神经元表现出活性依赖性突触前减少的突触能突触传递。虽然GLS 1基因敲除小鼠出生后不久死亡，但具有一个功能性GLS 1等位基因的GLS 1单倍不足小鼠（GLS 1 hets）非常正常。引人注目的是，功能成像显示，小鼠在海马中具有局灶性代谢低下，主要涉及CA1亚区和下托，这与精神分裂症患者最近的成像结果完全相反。此外，当用促精神病药物攻击时，GLS 1 het小鼠表现出与精神分裂症恢复力一致的行为和神经化学表型。因此，降低谷氨酰胺酶活性似乎对精神分裂症具有治疗潜力。为了将这一发现转化为临床应用，我们建议测试GLS1 het小鼠实际上对一系列促精神分裂症损伤具有弹性的假设。使用组织特异性GLS 1缺失，我们将询问海马代谢低下是否源于海马中GLS 1的减少，以及这种调节是否足以产生弹性表型。为了开始理解精神分裂症的病理生理学的弹性表型的含义，我们将确定海马中的突触改变，这些突触改变是活动减退的基础。为了直接测试GLS 1抑制的治疗潜力，我们将在成年小鼠中诱导GLS 1单倍不足，做我们称之为遗传药物治疗的事情，以研究干预的急性和慢性影响。我们将在发育早期诱导GLS 1单倍不足，以探索早期干预和神经发育贡献的潜在益处。最后，我们将进行高通量筛选，以确定具有纳摩尔功效的小分子GLS 1抑制剂作为候选药物。GLS 1抑制不仅对精神分裂症有治疗潜力，而且对中风和其他涉及兴奋性毒性的神经退行性疾病也有治疗潜力，因此CNS活性GLS 1抑制剂可能具有广泛的治疗前景。总之，计划的临床前研究以及候选药物的鉴定应该为GLS 1抑制作为精神分裂症的新型药物疗法向临床试验的发展提供基础。 公共卫生相关性：我们最近产生了一组连贯的临床和基础研究结果，提出了一个假设，即药理学抑制磷酸盐激活的转氨酶，基因GLS1的产物，应证明治疗精神分裂症。我们建议使用GLS 1缺陷小鼠作为概念验证来测试这一假设。其目的是深入了解GLS 1抑制的治疗基础，阐明所涉及的电路，并获得必要的知识，以走向临床药物开发。

DESCRIPTION (provided by applicant): Dysregulated glutamatergic neurotransmission has been strongly implicated in the psychopathology of schizophrenia. Recent studies have highlighted the therapeutic promise of presynaptic reductions in glutamate transmission. We have shown that neurons from glutaminase (GLS1) knockout mice show an activity-dependent presynaptic reduction in glutamatergic synaptic transmission. While GLS1 knockout mice die shortly after birth, GLS1 haploinsufficient mice with one functional GLS1 allele (GLS1 hets) are remarkably normal. Strikingly, functional imaging reveals that the mice have focal hypometabolism in the hippocampus, mainly involving the CA1 subregion and the subiculum that is the exact inverse of recent imaging findings in patients with schizophrenia. Moreover, when challenged with pro-psychotic drugs, GLS1 het mice manifest behavioral and neurochemical phenotypes consistent with schizophrenia resilience. Thus, reducing glutaminase activity appears to have therapeutic potential for schizophrenia. To translate this discovery to clinical application, we propose testing the hypothesis that GLS1 het mice are in fact resilient to a range of pro-schizophrenic insults. Using tissue-specific GLS1 deletions, we will ask whether the hippocampal hypometabolism arises from the reduction in GLS1 in the hippocampus, and whether this modulation is sufficient to produce the resilience phenotype. To begin to understand the implications of the resilience phenotype for the pathophysiology of schizophrenia, we will identify the synaptic alterations in the hippocampus that underlie the hypoactivity profile. To test the therapeutic potential of GLS1 inhibition directly, we will induce GLS1 haploinsufficiency in adult mice, doing what we term genetic-pharmacotherapy, to investigate the acute and chronic effects of the intervention. We will induce GLS1 haploinsufficiency earlier in development to explore potential benefits of early intervention and neurodevelopmental contributions. Finally, we will do high-throughput screening to identify small-molecule GLS1 inhibitors with nanomolar efficacy as drug candidates. GLS1 inhibition has therapeutic potential not only for schizophrenia, but also for stroke, and other neurodegenerative disorders involving excitotoxicity, so a CNS-active GLS1 inhibitor will likely have broad therapeutic promise. In summary, the planned preclinical studies together with identification of drug candidates should provide the basis for movement of GLS1 inhibition towards clinical trials as a novel pharmacotherapy for schizophrenia. PUBLIC HEALTH RELEVANCE: We have recently generated a coherent set of clinical and basic findings raising the hypothesis that pharmacological inhibition of phosphate-activated glutaminase, the product of gene GLS1, should prove therapeutic in schizophrenia. We propose to test this hypothesis using GLS1-deficient mice as a proof of concept. The aims are to gain insight into the therapeutic basis for GLS1 inhibition, to elucidate the circuitry involved, and to gain the necessary knowledge for moving toward clinical drug development.