Taken together, this study provides evidence that chronic treatment with a S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, results in a normalization of age-dependent behavioral decline possibly through the release of growth factors (e.g., VEGF and BDNF), which in turn could underlie the increased proliferation of neural progenitors and facilitated maturation of young hippocampal neurons not only in adult animals but also in aged mice and AD mouse model. Here, BDNF is linked to Alzheimer disease.