Andrew A. Pieper, Shanhai Xie, Emanuela Capota, Sandi Jo Estill, Jeannie Zhong, Jeffrey M. Long, Ginger L. Becker, Paula Huntington, Shauna E. Goldman, Ching-Han Shen, Maria Capota, Jeremiah K. Britt, Tiina Kotti, Kerstin Ure, Daniel J. Brat, Noelle S. Williams, Karen S. MacMillan, Jacinth Naidoo, Lisa Melito, Jenny Hsieh, Jef De Brabander, Joseph M. Ready, Steven L. McKnight
An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3?/? mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging.