Serotonin (5-hydroxytryptamnine, 5-HT) is a monoaminergic neurotransmitter orchestrating a broad array of cognitive and behavioral processes in the adult brain. The early expression of its receptors during development and the requirement of maternal and placental sources of serotonin to the foetus have led to the hypothesis that 5-HT could act as growth regulator in the fine-tuning of specific morphogenetic events during neurodevelopment. Outcomes from genetic mouse models in which brain 5-HT homeostasis has been perturbed by targeting genes necessary for serotonin reuptake, metabolism or synthesis such as SERT, MAO-A and Tph2, respectively, support this hypothesis. However, evidence of a role for 5-HT in adulthood as a growth regulator or its requirement for maintenance of the proper neuronal circuitry, which is known to be susceptible to 5-HT imbalance during early postnatal stages, is still missing. To bridge this gap we used the Tph2 conditional knock-out (cKO) allele that allows an efficient abrogation of 5-HT synthesis in the adult brain, in combination with the Tph2::GFP allele, in which GFP reporter expression highlights 5-HT neuron fibers and somata. Beside previously reported data showing that the lack of brain serotonin in Tph2 knock-out (KO) mice deeply affects serotonergic circuitry development with a brain region-specific effect, the abrogation of 5-HT synthesis during adulthood produces alterations of serotonergic innervation in rostral brain targets matching those observed in mice with a life-long depletion of brain serotonin. Remarkably, we reported that restoring brain 5-HT signaling in both Tph2 KO and cKO mice by chronic administration of the serotonin precursor 5-hydroxytryptophan (5-HTP) results in a significant reduction in the extent of serotonergic fiber innervation defects, thus demonstrating an unexpectedly high degree of plasticity of the adult serotonergic system in response to changes of 5-HT homeostasis. Moreover, 3D computer-based analysis of serotonergic axon terminal morphology showed that imbalances in brain 5-HT content exert their growth regulatory activity on 5-HT axon terminals by promoting sprouting. Altogether these data demonstrate that a correct 5-HT homeostasis is life-long required to maintain the proper serotonergic innervation of specific rostral brain regions.
Imbalance of serotonin homeostasis during adulthood affects serotonergic neuronal circuitry
PRATELLI, MARTA;PELOSI, BARBARA;MIGLIARINI, SARA;PASQUALETTI, MASSIMO
2016-01-01
Abstract
Serotonin (5-hydroxytryptamnine, 5-HT) is a monoaminergic neurotransmitter orchestrating a broad array of cognitive and behavioral processes in the adult brain. The early expression of its receptors during development and the requirement of maternal and placental sources of serotonin to the foetus have led to the hypothesis that 5-HT could act as growth regulator in the fine-tuning of specific morphogenetic events during neurodevelopment. Outcomes from genetic mouse models in which brain 5-HT homeostasis has been perturbed by targeting genes necessary for serotonin reuptake, metabolism or synthesis such as SERT, MAO-A and Tph2, respectively, support this hypothesis. However, evidence of a role for 5-HT in adulthood as a growth regulator or its requirement for maintenance of the proper neuronal circuitry, which is known to be susceptible to 5-HT imbalance during early postnatal stages, is still missing. To bridge this gap we used the Tph2 conditional knock-out (cKO) allele that allows an efficient abrogation of 5-HT synthesis in the adult brain, in combination with the Tph2::GFP allele, in which GFP reporter expression highlights 5-HT neuron fibers and somata. Beside previously reported data showing that the lack of brain serotonin in Tph2 knock-out (KO) mice deeply affects serotonergic circuitry development with a brain region-specific effect, the abrogation of 5-HT synthesis during adulthood produces alterations of serotonergic innervation in rostral brain targets matching those observed in mice with a life-long depletion of brain serotonin. Remarkably, we reported that restoring brain 5-HT signaling in both Tph2 KO and cKO mice by chronic administration of the serotonin precursor 5-hydroxytryptophan (5-HTP) results in a significant reduction in the extent of serotonergic fiber innervation defects, thus demonstrating an unexpectedly high degree of plasticity of the adult serotonergic system in response to changes of 5-HT homeostasis. Moreover, 3D computer-based analysis of serotonergic axon terminal morphology showed that imbalances in brain 5-HT content exert their growth regulatory activity on 5-HT axon terminals by promoting sprouting. Altogether these data demonstrate that a correct 5-HT homeostasis is life-long required to maintain the proper serotonergic innervation of specific rostral brain regions.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
