Abstract
Dysregulations of the central serotoninergic system have been implicated in several psychopathologies, characterized by different susceptibility between males and females. We took advantage of tryptophan hydroxylase 2 (TPH2) deficient rats, lacking serotonin specifically in the brain, to investigate whether a vulnerable genotype can be associated with alterations of neuronal plasticity from the early stage of maturation of the brain until adulthood. We found a significant increase, in both gene and protein expression, of the neurotrophin brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) of adult TPH2-deficient (TPH2−/−) male and female rats in comparison to wild type (TPH2+/+) counterparts. Interestingly, a development-specific pattern was observed during early postnatal life: whereas the increase in Bdnf expression, mainly driven by the modulation of Bdnf isoform IV was clearly visible after weaning at postnatal day (pnd) 30 in both sexes of TPH2−/− in comparison to TPH2+/+ rats, at early stages (pnd1 and pnd10) Bdnf expression levels did not differ between the genotypes, or even were downregulated in male TPH2−/− animals at pnd10. Moreover, to establish if hyposerotonergia may influence the response to a challenging situation, we exposed adult rats to an acute stress. Although the pattern of corticosterone release was similar between the genotypes, neuronal activation in response to stress, quantified by the expression of the immediate early genes activity regulated cytoskeleton associated protein (Arc) and Fos Proto-Oncogene (cFos), was blunted in both sexes of animals lacking brain serotonin. Interestingly, although upregulation of Bdnf mRNA levels after stress was observed in both genotypes, it was less pronounced in TPH2−/− in comparison to TPH2+/+ rats. In summary, our results demonstrated that serotonin deficiency affects neuroplastic mechanisms following a specific temporal pattern and influences the response to an acute stress.
Highlights
Serotonin 5-hydroxytryptamine (5-HT) was originally discovered as cardiovascular hormone but has later gained prominence as neurotransmitter or neuromodulator widely distributed in the central nervous system (CNS) and peripheral nervous systems
Post hoc analysis revealed an increase of total Bdnf mRNA levels both in tryptophan hydroxylase 2 (TPH2)−/− male rats (+23%, p < 0.05 vs. TPH2+/+) and in TPH2−/− female rats (+25%, p < 0.05 vs. TPH2+/+)
To assess if the changes in total Bdnf mRNA were paralleled by alterations in brain-derived neurotrophic factor (BDNF) protein, we investigated the levels of the mature form of BDNF in crude synaptosomal fraction (Figure 1B)
Summary
Serotonin 5-hydroxytryptamine (5-HT) was originally discovered as cardiovascular hormone but has later gained prominence as neurotransmitter or neuromodulator widely distributed in the central nervous system (CNS) and peripheral nervous systems. 5-HT biosynthesis occurs from the essential aminoacid tryptophan in two steps, and tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in this process. As it has been discovered in 2003 (Walther et al, 2003), 5-HT is produced by two different enzymes, TPH1 and TPH2, in the gut and in the brain, respectively. Since in adulthood it cannot pass the blood-brain barrier, these two enzymes define two 5-HT systems with independent regulation and different function. In the early phases of embryonic and postnatal life, 5-HT is a trophic factor that modulates cell proliferation, migration and differentiation in the brain and in peripheral tissues (Azmitia, 2001; Buznikov et al, 2001; Gaspar et al, 2003) and cell survival and synaptogenesis, through its role in the connective organization of the CNS (Gaspar et al, 2003)
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