The function of serotonin as a mood regulator is well known, and both serotonin itself and drugs that activate its signalling pathway have been used successfully to treat depression and anxiety disorders. However, the role of serotonin in establishing normal responses to anxiety-inducing stimuli has been unclear. Now, by manipulating the expression of a serotonin receptor in mice, Gross et al. have brought us one step closer to understanding this role.

To measure anxiety levels in mice, the authors studied their behaviour in an open field or an 'elevated-plus maze'. Mice generally prefer to be in a 'safe' environment, such as in the closed arms of the maze or at the sides of the open-field box, but their natural curiosity causes them to explore more aversive environments, such as the open arms of the maze or the centre of the open field. Their level of anxiety is determined by the amount of time that they spend exploring the aversive compartment of the apparatus; the more adventurous the mouse, the less anxious it is perceived to be.

It was previously shown that a global knockout of the serotonin1A receptor (5-HT1AR) causes an increase in anxiety-like behaviour in adult mice. By engineering a conditional knockout line in which the receptor gene could be selectively reactivated in the forebrain, Gross et al. were able to rescue this phenotype, allowing the mice to behave normally in response to anxiety-inducing situations. This result indicated that 5-HT1AR activity at its other main site of expression, the raphe nuclei of the brainstem, is not needed to reverse the anxiety phenotype in the knockout mice.

Another property of this 'rescued' mouse line was that 5-HT1AR expression could be switched off again by treating the mice with the antibiotic doxycycline. Gross et al. compared the effects of inactivating the receptor during late embryonic/early postnatal development and during adulthood. If the receptor was inactivated in adult mice, their responses to anxiety-inducing stimuli were indistinguishable from those of wild-type mice. By contrast, if the receptor was inactivated during development, the adult mice behaved like knockout mice, even when 5-HT1AR expression was restored at postnatal day 21. This result, combined with the observation that 5-HT1AR expression begins at postnatal day 5 in the rescued mice, indicates that there is a critical period between 5 and 21 days after birth when 5-HT1AR is required in the forebrain to establish normal anxiety responses. Failure to express the receptor during this period causes the mice to become excessively anxious in later life, but sustained expression in the adult mouse is not necessary to maintain a normal anxiety response.

The mechanism underlying this effect is as yet unknown, although 5-HT1AR has previously been implicated in synaptogenesis in the hippocampus and cortex, so it could be involved in establishing the neuronal circuits that are required for normal anxiety responses. Interestingly, in adults, chronic treatment with 5-HT1AR agonists can decrease anxiety, raising the possibility that similar mechanisms can be triggered in adulthood. Understanding these mechanisms should help in the design of more sophisticated therapies to treat anxiety disorders. It will also be interesting to look at factors that are believed to influence emotional well-being, such as maternal nurturing, and examine whether they affect 5-HT1AR activity during early life.