Pharmacological Enhancement of Adult Hippocampal Neurogenesis Improves Behavioral Pattern Separation in Young and Aged Male Mice

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. This manuscript describes a screening cascade using neural stem cells that enabled us to test more than 1 million compounds to identify compounds that could enhance neurogenesis: the growth of new neurons. Neurogenesis in the hippocampus facilitates behavioral pattern separation, which is the ability to discriminate between similar situations. The most promising compound to come out of the screen, RO6871135, was then tested in mice. We found that treatment with RO6871135 enhanced neurogenesis and also improved behavioral pattern separation in young and aged male mice. We then showed that RO6871135 works differently than existing medications that increase neuroge