Therapeutic potential of GLS1 inhibition for the pharmacotherapy of schizophrenia

描述（由申请人提供）：失调的谷氨酸能神经传递与精神分裂症的精神病理密切相关。最近的研究强调了突触前谷氨酸传递减少的治疗前景。我们已经证明，来自谷氨酰胺酶（GLS1）敲除小鼠的神经元在谷氨酸能突触传递中显示出活性依赖性的突触前减少。虽然GLS1基因敲除小鼠在出生后不久就会死亡，但GLS1单倍不足的小鼠具有一个功能GLS1等位基因（GLS1表）是非常正常的。引人注目的是，功能成像显示小鼠海马有局灶性代谢低下，主要涉及CA1亚区和下托，这与最近精神分裂症患者的成像结果完全相反。此外，当使用促精神病药物时，GLS1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具有治疗精神分裂症的潜力。为了将这一发现转化为临床应用，我们建议测试GLS1小鼠实际上对一系列促精神分裂症损伤具有弹性的假设。利用组织特异性GLS1缺失，我们将探讨海马低代谢是否源于海马中GLS1的减少，以及这种调节是否足以产生弹性表型。为了开始理解恢复表型对精神分裂症病理生理的影响，我们将确定海马体中构成低活动特征的突触改变。为了直接测试GLS1抑制的治疗潜力，我们将在成年小鼠中诱导GLS1单倍体功能不全，进行我们所谓的遗传药物治疗，以研究干预的急性和慢性效应。我们将在发育早期诱导GLS1单倍体功能不全，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GLS1抑制剂作为候选药物。GLS1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毒性的神经退行性疾病也有治疗潜力，因此cns活性GLS1抑制剂可能具有广泛的治疗前景。总之，计划中的临床前研究以及候选药物的确定应该为GLS1抑制作为精神分裂症的新药物治疗走向临床试验提供基础。

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.