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

选择性5-羟色胺再摄取抑制剂(SSRIs)是治疗抑郁和焦虑的一线药物，因此也是初级保健和精神病学中使用最广泛的药物疗法之一。他们的作用模式是增加大脑中神经递质5-羟色胺(5-HT)的水平，并通过一系列靶点改善这些衰弱的心理障碍的症状。然而，神经系统的正常发育和功能依赖于各种神经递质系统之间的平衡，而升高的5-羟色胺水平可能会产生非靶点效应。对于正在服用SSRIs以控制抑郁的孕妇来说，这是一个特别令人担忧的问题：SSRIs将穿过胎盘，导致胎儿在大脑发育的关键阶段5-羟色胺水平升高；这一阶段在很大程度上是由5-羟色胺与其他神经递质共同驱动的。由此产生的根本问题是，升高的5-羟色胺水平是否足以改变发育，从而影响大脑发育。目前，关于这一问题的研究存在分歧，一些小组发现，怀孕期间使用SSRI会导致后代患有自闭症和ADHD。虽然其他研究表明，SSRI本身并不是问题所在，但更多的是与母亲遗传的遗传因素有关。如果我们接受后者，那么在怀孕期间使用SSRI可能是有益的，而如果我们接受前者，那么孕妇不应该服用SSRI，即使这可能会对她们的精神健康产生重大影响，并可能导致同样糟糕的结果。我们的建议是使用模型系统直接解决这个问题。这种方法的好处是，我们可以将遗传因素(母体背景)与环境因素(由于SSRIs导致的5-羟色胺水平升高)分开，并直接评估后者对回路形成和紧急知觉的影响。我们的假设是，升高的5-羟色胺将导致早期电路异常--目前公布的证据表明确实如此，但新生儿的大脑有足够的可塑性来克服这种早期的侮辱。通过跟踪大脑发育并使用一系列先进的光学和电生理技术，我们应该能够区分个别细胞类型对紧急认知的贡献，并准确地了解任何功能障碍是如何以及何时出现的。最终，这项研究计划将帮助我们了解SSRI如何影响发育中的大脑，以及5-羟色胺升高的后果是否会在认知改变中表现出来，这些改变可能会支持自闭症和ADHD等令人衰弱和痛苦的情况。更具体地说，我们希望这项研究的结果在决定在这一脆弱的孕妇群体中开出或停用SSRI药物时，能更好地告知我们的临床同事。

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.