GABA receptors containing 5 subunits (GABA5) are highly expressed in the hippocampus and negatively involved in memory processing, as shown by the fact that GABA5-deficient mice show higher hippocampus-dependent performance than wild-type mice. Accordingly, small-molecule GABA5 negative allosteric modulators (NAMs) are known to enhance spatial learning and memory in rodents. Here we introduce a new, orally available GABA5 NAM that improves hippocampal functions. ONO-8590580 [1-(cyclopropylmethyl)-5-fluoro-4-methyl--[5-(1-methyl-1H-imidazol-4-yl)-2-pyridinyl]-1H-benzimidazol-6-amine] binds to the benzodiazepine binding sites on recombinant human 5-containing GABA receptors with a of 7.9 nM, and showed functionally selective GABA5 NAM activity for GABA-induced Cl channel activity with a maximum 44.4% inhibition and an EC of 1.1 nM. In rat hippocampal slices, tetanus-induced long-term potentiation of CA1 synapse response was significantly augmented in the presence of 300 nM ONO-8590580. Orally administered ONO-8590580 (1-20 mg/kg) dose-dependently occupied hippocampal GABA5 in a range of 40%-90% at 1 hour after intake. In the rat passive avoidance test, ONO-8590580 (3-20 mg/kg, by mouth) significantly prevented (+)-MK-801 hydrogen maleate (MK-801)-induced memory deficit. In addition, ONO-8590580 (20 mg/kg, p.o.) was also effective in improving the cognitive deficit induced by scopolamine and MK-801 in the rat eight-arm radial maze test with equal or greater activity than 0.5 mg/kg donepezil. No anxiogenic-like or proconvulsant effect was associated with ONO-8590580 at 20 mg/kg p.o. in the elevated plus maze test or pentylenetetrazole-induced seizure test, respectively. In sum, ONO-8590580 is a novel GABA5 NAM that enhances hippocampal memory function without an anxiogenic or proconvulsant risk.

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were significant associations between memory test score and e4, age, education level, and gender. There was a significant e4 x age interaction (p¼0.03). We found no associations between e4+ and processing speed or attention, or between family history of e4+ and cognitive test scores. There were significant associations between self-reported memory problems and both e4+ (p<0.001) and family history of e4+ (p<0.001). We identified 2032 "likely prodromal" and 6227 "likely preclinical" participants for AD trials. Of those likely eligible participants who reported their e4 genotype (n¼1650), 16% of prodromal and 4% of preclinical were e4+. Conclusions: In a large, novel, internet-based cohort, self-reported e4 is associated with online memory test scores in younger participants, and cognitively-normal participants. In the general cohort, age eclipses the effects of e4 genotype on memory scores. Self-reported memory problems are strongly associated with e4 even when controlling for other variables. BHR participants identified as likely prodromal have four times greater prevalence of e4+ than older adults with normal cognitive test scores. Self-report of e4 in BHR can be used to prescreen for AD trials requiring e4, facilitate AD trials, and accelerate development of new AD treatments.