Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult

Abstract

Serotonin is implicated in mood regulation, and drugs acting via the serotonergic system are effective in treating anxiety and depression. Specifically, agonists of the serotonin1A receptor have anxiolytic properties, and knockout mice lacking this receptor show increased anxiety-like behaviour. Here we use a tissue-specific, conditional rescue strategy to show that expression of the serotonin1A receptor primarily in the hippocampus and cortex, but not in the raphe nuclei, is sufficient to rescue the behavioural phenotype of the knockout mice. Furthermore, using the conditional nature of these transgenic mice, we suggest that receptor expression during the early postnatal period, but not in the adult, is necessary for this behavioural rescue. These findings show that postnatal developmental processes help to establish adult anxiety-like behaviour. In addition, the normal role of the serotonin1A receptor during development may be different from its function when this receptor is activated by therapeutic intervention in adulthood.

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…While interference with this process may alter the development of sensory circuits, the functional role of 5-HT release from thalamocortical fibers in depression and anxiety has not been investigated. In this context, it is important to note that anxiety-related behavioral deficits in 5HT-1 A knockout mice are due to the lack of serotonin action during development, and not in the adult (Gross et al, 2002).…”

Advances in behavioral genetics: mouse models of autism

“…177 The consequences of other alterations in 5-HT signaling can be seen in the phenotypes of mouse lines bearing targeted disruptions in the pathway. [42][43][44]178,179 Many of the genes involved in 5-HT signaling have been mutated in the mouse, including receptors, metabolic and catabolic enzymes, SERT, and others. Most of these cause behavioral changes related to anxiety, depression, and aggression.…”

“…Conditional expression of 5-HT 1A in hippocampal and cortical regions is sufficient to normalize anxietylike behavior in mutant mice. 178 Interestingly, the conditional loss of forebrain 5-HT 1A function does not induce the anxiety-like phenotype when the deletion 174,175 Receptor tyrosine kinase signaling, typified by BDNF (brain-derived neurotrophic factor), is shown in yellow. BDNF or other ligand binds a homo-or heterodimer of the receptor (for example, TrkB) that, in turn, phosphorylates proteins downstream, such as GRB2 (growth factor receptor-bound protein).…”

“…occurs in adulthood. 178 Furthermore, adult mice with loss of 5-HT 1A function do not have enhanced anxiety-like behavior if 5-HT 1A expression occurred earlier in life, between postnatal day 5 and 80. 178 This is an elegant example of how normal adult behavior may be dependent on signaling events early in development.…”

Sex Differences in the Regulation of Serotonergic Transmission and Behavior in 5-HT Receptor Knockout Mice

“…Thus, although the behavioral phenotype between 5-HT 1A and 5-HT 1B receptor knockout mice appeared similar, it was caused for different reasons. The reduced immobility of male and female 5-HT 1A receptor knockout mice is caused by compensations due to the constitutive loss of 5-HT 1A receptors during development, because the conditional deletion of 5-HT 1A receptors during maturity fails to produce the same behavioral phenotype (Gross et al, 2002;Lucki, unpublished data). In contrast, the antidepressantlike phenotype of female 5-HT 1B receptor knockout mice was likely caused by higher baseline 5-HT levels in female 5-HT 1B knockout mice and this was a necessary requisite for the reversal of the behavioral phenotype by depletion of 5-HT produced by PCPA administration.…”