Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety

Abstract

Identifying the factors contributing to the etiology of anxiety and depression is critical for the development of more efficacious therapies. Serotonin(5-HT)isintimatelylinkedtobothdisorders.Theinhibitoryserotonin-1A (5-HT1A)receptor exists in two separate populations with distinct effects on serotonergic signaling: (1) an autoreceptor that limits 5-HT release throughout the brain and (2) a heteroreceptor that mediates inhibitory responsestoreleased5-HT. Traditional pharmacologic and transgenic strategies have not addressed the distinct roles of these two receptor populations. Here we use a recently developed genetic mouse system to independently manipulate 5-HT1A autoreceptor and heteroreceptor populations. Weshow that 5-HT1A autoreceptors acttoaffect anxiety-like behavior.Incontrast, 5-HT1A heteroreceptors affect responses to forced swim stress, without effects on anxiety-like behavior. Together with our previously reported work, these results establish distinct roles for the two receptor populations, providing evidence that signaling through endogenous 5-HT1A autoreceptors is necessary and sufficient for the establishment of normal anxiety-like behavior. © 2011 the authors.