Establishment of a novel animal model of depression by inhibiting serotonin synthesis using in vivo gene editing

Abstract

The serotonin hypothesis of depression has existed since over 50 years ago. However, it remains unclear whether decreased serotonin levels in the brain could cause depression mainly because of ethical or technical limitations. For example, we and others have demonstrated using optogenetic or chemogenetic methods that two origins of serotonergic projections to the forebrain, the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), play distinct roles in cognitive and emotional function (Ohmura et al., 2014, Int J Neuropsychopharmacol; Teissier et al. 2015, Cell Rep; Ohmura et al., 2020, Neuropharmacology; Ohmura et al., 2021, Curr Biol), indicating that selective manipulation of each nucleus is required. Moreover, recent studies showed that serotonin neurons release glutamate as well as serotonin, suggesting that previous studies have failed to manipulate serotonin levels selectively. To overcome the above limitations, we separately knocked out the tryptophan hydroxylase 2 (TPH2) gene in each serotonergic origin (DRN and MRN) by taking advantage of in vivo gene editing with CRISPR/Cas9 and examined whether the reduction of serotonin in each nucleus could induce depression-like behavior in adult mice.