The brain synaptic circuitry is shaped during maturation by both physiological and environmental cues, and alterations in circuit assembly are associated with susceptibility to neuropsychiatric disorders. Reduced function of serotonin uptake transporter (SERT) during development increases the risk of neuropsychiatric disorders, but little is known about its temporal control and impact on circuit assembly. Now, Ji Sze and colleagues discover that SERT is important for hippocampal synaptic circuit maturation with sex-biased impacts. They find that SERT is expressed in CA3 pyramidal neurons during a key period of hippocampal circuit maturation. In mice with SERT deleted in the hippocampal pyramidal neurons (SERTpyramidalΔ), the authors observe a reduced density of thin-type spines on the connecting CA1 neurons in juveniles, but an increase in the density of mushroom-shaped spines in adults. Although the mutant mice show no defects in presynaptic release probability, the magnitude of stimulus-evoked long-term potentiation is significantly elevated in females, while long-term depression is diminished in both sexes. The sex-biases extend to transcriptional alterations in the hippocampus and cognitive behavioural defects, with both shared and distinct changes in SERTpyramidalΔ male and female mice. Together, these data demonstrate that SERT is involved in directing normal sex-dimorphic circuit development in the hippocampus during a precise window of development.
