Impact of early life SSRI exposure on neural circuit formation and function

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Selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression and anxiety and as such, one of the most widely used drug therapies in primary care and psychiatry. Their mode of action is to increase the levels of the neurotransmitter serotonin (5-HT) in brain and through a constellation of targets ameliorate the symptoms of these debilitating psychological disorders. However normal development and function of the nervous system is dependent on balance between a variety of neurotransmitter system and elevated levels of 5-HT might have off-targets effects. This is a particular concern in pregnant women who are taking SSRIs to control depression: SSRIs will cross the placenta and lead to elevated levels of 5-HT in the foetus at a critical stage in brain development; a stage very much driven by 5-HT in concert with other neurotransmitter. The fundamental question this gives rise to is whether the elevated 5-HT levels alter development sufficiently to impact on brain development. At present, research is divided on this issue with some groups finding that SSRI use during pregnancy can result in autism and ADHD in the offspring. While other studies suggest that the SSRIs themselves are not the issue, rather that there is more of a link with genetic factors inherited from the mother. If we accept the latter, then SSRI use is probably beneficial during pregnancy while if we accept the former then pregnant women should not take SSRIs even though this might have significant implications for their mental well-being and potentially lead to an equally poor outcome. Our proposal is to address this question directly using a model system. The benefit of this approach is that we can separate genetic (maternal background) from environmental factors (elevated 5-HT levels due to SSRIs) and directly assess the impact of the the latter on circuit formation and emergent perception. Our hypothesis is that elevated 5-HT will result in early circuit abnormalities - current published evidence suggest that this is the case, but that the neonatal brain is sufficient plastic to overcome this early insult. By tracking brain developing and using an array of advanced optical and electrophysiological techniques, we should be able to prise apart the contribution of individual cell types to emergent cognition and understand exactly how and when any dysfunction arises. Ultimately, this programme of research will help us understand how SSRIs influence the developing brain and whether or not the consequences of elevated 5-HT manifest in altered cognition that could underpin conditions as debilitating and distressing as autism and ADHD. More specifically, we hope that the results of this study will better inform our clinical colleagues when making the decision to prescribe or withdraw SSRI medication in this vulnerable population of pregnant women.