TPH1-dependent maternal hyposerotonemia: long-term effects on adult wild-type mouse offspring

Numerous mood and behavior disorders have developmental origins resulting from genetic and environmental interactions. Maternal tryptophan hydroxylase 1 (TPH-1)-dependent serotonin (5-HT) depletion alters embryonic brain development, but its long-term impact on adult progeny has never been investigated. Here we demonstrate that adult WT male offspring born to hyposerotonergic Tph1^+/- dams ( ~ 60% deficit) display hyperlocomotion, impaired self-care and an increased anxiety relative to those from WT dams. Concomitantly, norepinephrine (NE) levels and dopamine (DA) turnover are significantly reduced in the mesencephalon and brainstem, whereas monoaminergic cell density is not affected. In the frontal cortex of the offspring, maternal hyposerotonergic status results in significant reduction in DA, NE and 5-HT levels, accompanied by transcriptomic changes, notably in monoaminergic system signaling, synaptic function and plasticity, methylation processes and myelination. Myelination is also impaired as revealed by a reduced thickness of the corpus callosum. Maternal hyposerotonemia thus appears sufficient to affect the phenotype of the adult WT progeny. TPH-1-dependent 5-HT deficit during pregnancy could be considered as a risk factor for neurodevelopmental disorders in the offspring.