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

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.

SSRIs are the first-line treatment for depression and one of the most widely used drug therapies in primary care. However, the impact of elevated 5-HT on brain development is poorly understood and it remains unclear whether pregnant women should continue SSRI treatment, given the possible implications for the cognitive abilities of the offspring. To address this we will use a model system in which we can separate genetic (maternal background) from environmental factors (elevated 5-HT due to SSRIs) and directly assess the impact of the latter on circuit formation and emergent perception. Our hypothesis is that elevated 5-HT will result in early circuit abnormalities but that the neonatal brain is sufficient plastic to overcome this early insult.

As such, our objective is to test the impact of SSRIs from the cellular to the system levels. We will employ genetic technologies to identify the contribution of neurons altered by 5-HT dysfunction to the developing circuit in vitro, mapping their synaptic connections through early postnatal life. In parallel, we will use optical techniques to assess the consequences for local excitatory-inhibitory balance. Combined these experiments will provide the platform for subsequent investigations that will assess the impact of altered 5-HT signalling on both sensory-evoked and spontaneous activity in vivo, giving us significant insight on global alterations in neonatal cognition. Finally, we will employ 3-photon imaging to pioneer chronic imaging across the depth of the developing cortical column, record population activity, and thereby establish the impact of altered 5-HT signalling on the dynamics of emergent perception. Together this will provide a detailed picture of the impact of SSRI exposure on brain development with significant translational value for humans. We believe that this proposal is highly relevant to current MRC strategy which prioritises the application of fundamental science to address key mental health issues.

The current proposal represents an important step in a programme of research that we hope will significantly influence our understanding of the impact of SSRIs on brain development. The builds on our existing research that has employed developmental genetics and LSPS to map the basic circuitry of the developing neocortex in normal brains. To date we have published three papers from this series with a further four ready for dissemination to the academic community within the next year. In total, this body of work will provide a detailed assessment of how the normal brain comes online including studies into the earliest subplate circuits, the contribution of all major subtypes of interneuron (including VIP+ cells) to early networks across cortical areas as well as emergent in vivo properties of these cells. This combined body of work provide the ideal platform for the further investigation of the consequences of network dysfunction and our ultimate objective of translating the knowledge to development human neuro-pathophysiology. As such, we envisage that the impact of the current study will be three-fold:

(1) fundamental research into brain development;
(2) researchers interested in the role of serotonin neurotransmission in brain function;
(3) clinicians who regularly prescribe SSRIs to treat depression and anxiety disorders in their patient population.

In relation to the latter, we have already reached out to and agreed to communicate our findings from this project to the specialist teams in Foetal Medicine and Perinatal Psychiatry at the John Radcliffe Hospital. We hope that this interaction will lead to further investigations into the use and efficacy of SSRIs (a broad class of drug) in pregnant women and indeed other patient cohorts. In addition, we have been working with the Pharmaco-Epidemiology team in the Centre for Statistics in Medicine, NDORMS (Oxford University), to better understand current use of SSRIs in the population and pregnant women in particular.

In terms of fundamental science, a number of groups are already exploring the impact of serotonin neurotransmission on brain development. We believe we can make a significant contribution to this field with our focus on GABAergic interneurons and excitatory-inhibitory balance. Our use of a combined in vitro and in vivo electrophysiology approach - now augmented with advanced in vivo imaging - will we believe shed significant new insights into how multiple neurotransmitter systems interact to sculpt emergent perception. We believe this will be of interests not only to researchers exploring the role of serotonin in the brain but also the wider field of neuroscience. From a purely developmental perspective, we have an amazing array of technologies that provide us with an almost unparalleled ability to better define the complexity of the developing brain. This study represents an important step in expanding our knowledge of how specific classes of neuron acquire functionality to underpin higher-order cognitive activity in humans and how a common class of drugs - SSRIs - impact on that trajectory.