Serotonergic neurotransmission manipulation for the understanding of brain development and function: Learning from Tph2 genetic models

Serotonin (5-hydroxytriptamine; 5-HT) is a fascinating neurotransmitter that thanks to an extensive axonal network is released throughout the entire central nervous system (CNS) and exerts its action on the modulation of a countless number of physiological, behavioral and cognitive processes. In addition, cumulating evidences have linked alteration in 5-HT neurotransmission with the onset of psychiatric and neurodevelopmental disorders, such as depression, autisms and schizophrenia. Nevertheless only 5% of the total body content of serotonin exerts its action in the CNS, while the rest is synthetized and stored in peripheral tissues where it acts as an autacoid. In 2003 it became evident that two distinct isoforms of tryptophan hydroxylase (Tph), the rate-limiting enzyme for the synthesis of serotonin, are selectively expressed in peripheral tissues and in the CNS, with Tph2 as the brain specific isoform. In the present review we describe how the discovery of Tph2 has improved our understanding on the role of serotonergic neurotransmission. We mainly focus on the analysis of animal models generated by genetic manipulation of Tph2, in which the synthesis of brain serotonin was either reduced or disrupted. The consequences of an altered serotonergic neurotransmission on brain development, as well as on physiological and behavioral processes will be assessed. Finally, we report on several association studies that have linked single nucleotide polymorphisms (SNPs) in the human TPH2 gene with behavioral disturbances and neuropsychiatric disorders