Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation

Abstract

Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knock-in mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region- and time- specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2∷eGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

“…We argue that increased BNDF levels in these animals may reflect a compensatory mechanism of the brain in the absence of serotonin. Our study confirms and extends to the protein level the results by Migliarini and co-workers [29]. They reported increased BDNF gene transcription in the hippocampus of a knock-in mouse line in which the Tph2 gene is replaced by enhanced green fluorescent protein (eGFP).…”

“…They reported increased BDNF gene transcription in the hippocampus of a knock-in mouse line in which the Tph2 gene is replaced by enhanced green fluorescent protein (eGFP). However, in that study, BDNF mRNA expression changes were rather subtle and did not yield statistically significant differences in the cortex [29]. Our results are also directly relevant to the situation in the human brain, where a loss-of-function mutation in the Tph2 gene has been described resulting in an approximately 80% decrease in serotonin production [30].…”

The role of serotonin in adult hippocampal neurogenesis

“…-/-and Tph2KI mice (Migliarini et al, 2012, Sachs et al, 2013, although accompanied by increased serotonin fiber density in the hilus. Nevertheless, whether BDNF signaling is related to the clinical features of depression and whether distinct antidepressants directly affect BDNF equally to serotonin remains unknown.…”

“…Noticeable, serotonergic neurons and fibers persist in the adult brain of serotonindepleted mice (Gutknecht et al, 2008, Alenina et al, 2009, Migliarini et al, 2012 raising the question of their functional role when serotonin is absent. The neuromodulator character of serotonin affects excitatory or inhibitory release mediated by glutamate or GABA (Schmitz et al, 1995, Li et al, 2000 with one study showing that serotonergic neurons itself can express the GABA-synthesizing enzyme glutamic acid decarboxylase (Fu et al, 2010).…”

“…We suggested population changes on the cellular level in the absence of serotonin as potential compensatory mechanism that maintains the progenitor cell pool and thus homeostasis in Tph2 -/-mice. Whether compensation is also due to adaptations at the level of 5-HT receptors and their downstream pathways, or alterations in neurotrophic factor signaling such as an increase in hippocampal brain-derived neurotrophic factor (BDNF) expression (Migliarini et al, 2012, Sachs et al, 2013 induced by developmental deficiency in brain serotonin needs to be determined. In the model of congenital serotonin deficiency (Tph2KI), increased numbers of DCX-expressing cells have been found showing a shift towards late-stage progenitor cells (Sachs et al, 2013).…”