Abstract
Neurotrophic factors are relevant regulators of the neurogenic process at different levels. In particular, the brain-derived neurotrophic factor, BDNF, is highly expressed in the hippocampus (HC) of rodents and participates in the control of neuronal proliferation, and survival in the dentate gyrus (DG). Likewise, serotonin is also involved in the regulation of neurogenesis, though its role is apparently more complex. Indeed, both enhancement of serotonin neurotransmission as well as serotonin depletion, paradoxically increase neuronal survival in the HC of mice. In this study, we analyzed the protein expression of the BDNF isoforms, i.e., pro- and mature-BDNF, and their respective receptors p75 and TrkB, in the HC of mice chronically treated with para-chloro-phenyl-alanine (PCPA), an inhibitor of serotonin synthesis. The same analysis was conducted in hyposerotonergic mice with concomitant administration of the 5-HT1A receptor agonist, 8-Hydroxy-2-(di-n- propylamino) tetralin (8-OH-DPAT). Increased expression of p75 receptor with decreased expression of pro-BDNF was observed after chronic PCPA. Seven-day treatment with 8-OH-DPAT reestablished the expression of pro-BDNF modified by PCPA, and induced an increase in the expression of p75 receptor. It has been demonstrated that PCPA-treated mice have higher number of immature neurons in the HC. Given that immature neurons participate in the pattern separation process, the object pattern separation test was conducted. A better performance of hyposerotonergic mice was not confirmed in this assay. Altogether, our results show that molecules in the BDNF signaling pathway are differentially expressed under diverse configurations of the serotonergic system, allowing for fine-tuning of the neurogenic process.
Highlights
With the extension of life expectancy, several pathologies affecting the central nervous system have gained greater visibility
Whereas no significant differences were found between experimental groups for mature BDNF (mBDNF), its receptor TrkB, and proBDNF, expression of the proBDNF receptor, p75, was significantly increased (p = 0.0427) in PCPAtreated mice
One week administration of DPAT in vehicle-treated mice induced a significant decrease in the expression of mBDNF (p = 0.0403) and TrkB receptor (p = 0.0004), without significantly affecting the levels of proBDNF or p75 receptor
Summary
With the extension of life expectancy, several pathologies affecting the central nervous system have gained greater visibility. In this context, disentangling the etiopathogenesis of neurodegenerative diseases and seeking for more effective therapies represent key challenges. A thorough knowledge of the molecular mechanisms controlling neurogenesis and its possible manipulation in pathological conditions is required in view of its therapeutic use. In this sense, neurotrophic factors have recently emerged as regulators of the neurogenic process at different levels (see review in Vilar and Mira, 2016). The actions of both BDNF isoforms contribute to the regulation of neuronal homeostasis
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