The Butt lab, working in collaboration with Trevor Sharp (Pharmacology, Oxford), Adam Packer (Meta Reality Labs) and Yulong Li (Peking University School of Life Sciences), has published a study in Nature Communications on how changes in serotonin signalling affect perinatal brain development. Funded by the Medical Research Council and the EU Horizon 2020 programme, this project set out to better understand the impact of maternal SSRI anti-depressant use on neural circuit formation and function in the developing brain of the foetus; an important question given such exposure in utero has been linked to a higher risk of conditions like autism and ADHD in offspring.
To distinguish between the effects of the drug and residual confounds such as maternal diagnosis, the team developed a longitudinal, 2-photon in vivo imaging approach in mice that enabled them to track either serotonergic signalling or neural activity in individual pups across development. They studied how either SSRI anti-depressants, genetic deletion of the serotonin transporter, or early-life stress affected how neonatal mice process touch in somatosensory cortex. They found that healthy brain development in early life relies on low serotonin levels, supported by REM sleep and normal serotonin transporter activity. When this balance was disrupted—by SSRIs or genetic changes— the resultant increase in serotonin signalling blocked sensory instruction of developing cortex. Ultimately, this compromised the development of GABAergic inhibition and a switch from hypo- to hyperactivity midway through the second postnatal week, just as the pups began to actively sense their environment. In animals with genetic deletion of the serotonin transporter, they observed compensation in neural activity later on in life. However, those dosed with SSRI as neonates never recovered, with hyperactivity present through to adulthood.
Simon Butt comments, 'Our hope is that this study will better inform clinical practice, with further research needed to understand if non-serotonergic drugs present a better route for the treatment of depression in pregnant women. From a fundamental science perspective, our development of this longitudinal imaging platform provides us with unparalleled access to the activity and function of individual, genetically identified neurons across the lifespan of an animal. This means we can follow day-to-day the trajectory of mouse models ranging from autism to Alzheimer’s disease and then, in our analysis, rewind time to identify and design interventions targeted at critical moments in the aetiology of these conditions.'
Members of the Butt lab who contributed to the study are Gabriel Ocana-Santero, Hannah Warming, Veronica Munday, Heather MacKay, Caius Gibeily, Christopher Hemingway, Jacqui Stacey, Abhishek Saha, Ivan Lazarte and Anjali Bachetta.