Altered anxiety-related behavior in mice treated with benzodiazepines during postnatal development

TSETSENIS T; DEPINO AM; GROSS C

Washington DC, Estados Unidos

Congreso; 35th Annual Meeting of the Society for Neuroscience; 2005

Society for Neuroscience

Proper levels of neural excitability are essential for normal brain function. During development, neurons are challenged with perturbations that cause increases and decreases in neural excitability. In vitro studies have described homeostatic plasticity mechanisms that are able to compensate for such perturbations and keep neural excitability within the normal range. In the visual system homeostatic plasticity has been shown to be critical for maintaining correct neuronal excitability in vivo. Our aim was to test whether homeostatic plasticity is a general phenomenon also active in brain circuits modulating anxiety-related behavior. In addition, we sought to determine whether homeostatic plasticity could be involved in the long-term behavioral consequences of early development interventions. To test these hypotheses we treated mice from P14 to P28 with the benzodiazepine diazepam and assessed anxiety-related behavior in adulthood. We chose this period because the third and fourth postnatal weeks are a period of dramatic excitatory and inhibitory synaptogenesis in forebrain structures controlling anxiety-related behavior. We avoided treating mice during the first two postnatal weeks when GABA is primarily excitatory. As expected, we observed anxiolytic effects of the drug following one day of treatment, an effect that was reversed after two weeks of chronic treatment. Two weeks after discontinuation of the treatment no differences were observed among experimental groups. However, one month after the end of treatment diazepam-treated mice exhibited significantly reduced anxiety-related behavior in the open-field and elevated plus maze tests. Our results support the idea that increasing GABA function early in life can induce persistent changes in brain function that can lead to long-term behavioral changes. The fact that early diazepam treatment is associated with decreased anxiety-related behavior in adulthood however, appears to contradict the simple hypothesis that homeostatic plasticity can counteract the effects of increased inhibition in these circuits.