Perturbation of Serotonin Homeostasis during Adulthood Affects Serotonergic Neuronal Circuitry

Abstract

Growing evidence shows that the neurotransmitter serotonin (5-HT) modulates the fine-tuning of neuron development and the establishment of wiring patterns in the brain. However, whether serotonin is involved in the maintenance of neuronal circuitry in the adult brain remains elusive. Here we use a Tph2^fl°^x conditional knockout (cKO) mouse line to assess the impact of serotonin depletion during adulthood on serotoninergic system organization. Data show that the density of serotonergic fibers is increased in the hippocampus and decreased in the thalamic paraventricular nucleus (PVN) as a consequence of brain serotonin depletion. Strikingly, these defects are rescued following re-establishment of brain 5-HT signaling via administration of the serotonin precursor 5-hydroxytryptophan (5-HTP). Finally, 3D reconstruction of serotonergic fibers reveals that changes in serotonin homeostasis affect axonal branching complexity. These data demonstrate that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring.

Significance Statement Alterations in brain serotonin levels during development can interfere with neuronal circuitry establishment and contribute to behavioral disturbances in adult life. It remains enigmatic whether wiring patterns can be reshaped by fluctuations of 5-HT content in the adult brain. In this study we show for the first time that the adult serotonergic circuitry is susceptible to perturbations of serotonin homeostasis. These results provide evidence of life-long requirement of proper 5-HT levels to preserve the serotonergic axonal wiring.