Serotonergic gene inactivation in mice: models for anxiety and aggression?

Variation in genes coding for proteins that control serotonin (5-HT) system development, plasticity and function have been implicated in various aspects of complex behaviour including anxiety and aggression. Based on the remarkable progress in technologies that allow the alteration or elimination of individual genes to create transgenic animal models, gene knockout strategies further increase our knowledge about which serotonergic gene products are involved in behavioural traits. This overview selects anxiety and aggression as paradigmatic traits and behaviours, and focuses on mouse models which have been modified by deletion of genes coding for key players of serotonergic neurotransmission. In particular, phenotypic changes in mice bearing inactivation mutations of 5-HT1A and 5-HT1B receptors, 5-HT transporter, 5-HT neuron-specific transcription factor Pet1, monoamine oxidase A and genes related to 5-HT signalling will be discussed and major findings highlighted. However, because a missing gene might affect many developmental processes throughout ontogeny and compensatory mechanisms may be activated in knockouts, behavioural data from mice with targeted gene deletions should be interpreted with caution. The development of conditional knockout mice, in which a specific gene can be inactivated neurocircuit-specifically at any time, is therefore likely to avert the deficiencies associated with behavioural data from classical constitutive knockouts.