Chang Wei-Li, Tegang Karly, Samuels Benjamin A, Saxe Michael, Wichmann Juergen, David Denis J, David Indira Mendez, Augustin Angélique, Fischer Holger, Golling Sabrina, Lamerz Jens, Roth Doris, Graf Martin, Zoffmann Sannah, Santarelli Luca, Jagasia Ravi, Hen René
Department of Psychiatry, Division of Systems Neuroscience, Columbia University, New York State Psychiatric Institute, New York, New York.
Yale School of Medicine, New Haven, Connecticut.
Biol Psychiatry Glob Open Sci. 2024 Nov 20;5(2):100419. doi: 10.1016/j.bpsgos.2024.100419. eCollection 2025 Mar.
Impairments in behavioral pattern separation (BPS)-the ability to distinguish between similar contexts or experiences-contribute to memory interference and overgeneralization seen in many neuropsychiatric conditions, including depression, anxiety, posttraumatic stress disorder, dementia, and age-related cognitive decline. Although BPS relies on the dentate gyrus and is sensitive to changes in adult hippocampal neurogenesis, its significance as a pharmacological target has not been tested.
In this study, we applied a human neural stem cell high-throughput screening cascade to identify compounds that increase human neurogenesis. One compound with a favorable profile, RO6871135, was then tested in young and aged mice for effects on BPS and anxiety-related behaviors.
Chronic treatment with RO6871135 (7.5 mg/kg) increased adult hippocampal neurogenesis and improved BPS in a fear discrimination task in both young and aged mice. RO6871135 treatment also lowered innate anxiety-like behavior, which was more apparent in mice exposed to chronic corticosterone. Ablation of adult hippocampal neurogenesis by hippocampal irradiation supported a neurogenesis-dependent mechanism for RO6871135-induced improvements in BPS. To identify possible mechanisms of action, in vitro and in vivo kinase inhibition and chemical proteomics assays were performed. These tests indicated that RO6871135 inhibited CDK8, CDK11, CaMKIIa, CaMKIIb, MAP2K6, and GSK-3β. An analog compound also demonstrated high affinity for CDK8, CaMKIIa, and GSK-3β.
These studies demonstrate a method for empirical identification and preclinical testing of novel neurogenic compounds that can improve BPS and point to possible novel mechanisms that can be interrogated for the development of new therapies to improve specific endophenotypes such as impaired BPS.
行为模式分离（BPS）——区分相似情境或经历的能力——受损会导致在许多神经精神疾病中出现记忆干扰和过度概括，这些疾病包括抑郁症、焦虑症、创伤后应激障碍、痴呆症以及与年龄相关的认知衰退。尽管BPS依赖于齿状回且对成年海马神经发生的变化敏感，但其作为药物靶点的重要性尚未得到验证。
在本研究中，我们应用了一种人类神经干细胞高通量筛选流程来鉴定能增加人类神经发生的化合物。然后，对一种具有良好特性的化合物RO6871135在年轻和老年小鼠中进行测试，以观察其对BPS和焦虑相关行为的影响。
用RO6871135（7.5毫克/千克）进行慢性治疗可增加成年海马神经发生，并改善年轻和老年小鼠在恐惧辨别任务中的BPS。RO6871135治疗还降低了先天的焦虑样行为，这在暴露于慢性皮质酮的小鼠中更为明显。通过海马照射消除成年海马神经发生支持了RO6871135诱导的BPS改善的神经发生依赖性机制。为了确定可能的作用机制，进行了体外和体内激酶抑制以及化学蛋白质组学分析。这些测试表明RO6871135抑制了CDK8、CDK11、CaMKIIa、CaMKIIb、MAP2K6和GSK-3β。一种类似化合物也显示出对CDK8、CaMKIIa和GSK-3β具有高亲和力。
这些研究证明了一种经验性鉴定和临床前测试新型神经源性化合物的方法，这些化合物可以改善BPS，并指出了可能的新机制，可用于开发新疗法以改善特定的内表型，如受损的BPS。
