Perinatal serotonin signalling dynamically influences the development of cortical GABAergic circuits with consequences for lifelong sensory encoding

Gabriel Ocana-Santero, Hannah Warming, Veronica Munday, Heather A. MacKay, Caius Gibeily, Christopher Hemingway, Jacqueline A. Stacey, Abhishek Saha, Ivan P. Lazarte, Anjali Bachetta, Fei Deng, Yulong Li, Adam M. Packer, Trevor Sharp and Simon. J. B. Butt ()
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Gabriel Ocana-Santero: Oxford University
Hannah Warming: Oxford University
Veronica Munday: Oxford University
Heather A. MacKay: Oxford University
Caius Gibeily: Oxford University
Christopher Hemingway: Oxford University
Jacqueline A. Stacey: Oxford University
Abhishek Saha: Oxford University
Ivan P. Lazarte: Oxford University
Anjali Bachetta: Oxford University
Fei Deng: Peking University School of Life Sciences
Yulong Li: Peking University School of Life Sciences
Adam M. Packer: Oxford University
Trevor Sharp: Oxford University
Simon. J. B. Butt: Oxford University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Serotonin plays a prominent role in neurodevelopment, regulating processes from cell division to synaptic connectivity. Clinical studies suggest that alterations in serotonin signalling such as genetic polymorphisms or antidepressant exposure during pregnancy are risk factors for neurodevelopmental disorders. However, an understanding of how dysfunctional neuromodulation alters systems level activity over neocortical development is lacking. Here, we use a longitudinal imaging approach to investigate how genetics, pharmacology, and aversive experience disrupt state-dependent serotonin signalling with pathological consequences for sensory processing. We find that all three factors lead to increased neocortical serotonin levels during the initial postnatal period. Genetic deletion of the serotonin transporter or antidepressant dosing results in a switch from hypo- to hyper-cortical activity that arises as a consequence of altered cortical GABAergic microcircuitry. However, the trajectories of these manipulations differ with postnatal exposure to antidepressants having effects on adult sensory encoding. The latter is not seen in the genetic model despite a similar early phenotype, and a distinct influence of maternal genotype on the development of supragranular layers. These results reveal the dynamics and critical nature of serotonin signalling during perinatal life; pharmacological targeting of which can have profound life-long consequences for cognitive development of the offspring.

Date: 2025
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DOI: 10.1038/s41467-025-59659-5

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