TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner

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.

Centella asiatica L. Phytosome Improves Cognitive Performance by Promoting Bdnf Expression in Rat Prefrontal Cortex

“…Tissues were homogenized, and proteins were extracted as previously described [16]. The protein concentration of each sample was assessed according to the Bradford protein assay procedure (Bio-Rad Laboratories) with albumin as the calibration standard.…”

The Absence of Serotonin in the Brain Alters Acute Stress Responsiveness by Interfering With the Genomic Function of the Glucocorticoid Receptors

“…Adult male TPH2 +/+ and TPH2 −/− rats were exposed to acute restraint stress as previously described (Brivio et al, 2018;Calabrese et al, 2020). Briefly, rats were placed in an air-accessible apparatus for 1 h. The size of the container was similar to the size of the animal, making the rats almost immobile.…”

“…Psychiatric pathologies in humans have a multifactorial etiology with genetic and environmental factors that may interact thus inducing the manifestation of a wide range of symptoms McKinney, 1973, 1975). Among the genetic factors that can predispose to the development of psychiatric illnesses, such as depression, alterations in the serotonergic system are the most studied not only at clinical level but also in preclinical studies (Caspi et al, 2003;Calabrese et al, 2013;Brivio et al, 2018;Ottenhof et al, 2018). Interestingly, serotonergic projections innervate the paraventricular nucleus of the hypothalamus as well as the brain regions involved in the stress-induced activity of the HPA axis, including the prefrontal cortex (PFC) (Pan and Gilbert, 1992;Van de Kar et al, 2001;Herman et al, 2003).…”

“…On the contrary, acute stressors can have a positive impact on the brain leading to the activation of neuroplastic mechanisms and the transcription of activity-dependent genes (Brivio et al, 2020). In this context, we recently demonstrated that despite a normal corticosterone-release pattern upon acute stress, TPH2-deficiency in rats results in an up-regulation of the neurotrophin BDNF in basal conditions, but a blunted response to acute stress (Brivio et al, 2018).…”

Alterations in BDNF Protein Concentrations in the Hippocampus do not Explain the Pro-Neurogenic Effect of Citalopram on Adult Neurogenesis

“…This combination of symptoms mirrors important as pects of the clinical presentation of depressed patients with reduced central serotonin function (i. e., low 5-hydroxyindole ace tic acid levels in cerebrospinal fluid [13,14]). Using Tph2 − / − animals, we and others demonstrated that depletion of brain serotonin increases BDNF expression in hippocampus and prefrontal cortex [15][16][17] and that serotonin is required for the bi ological effects of electroconvulsive therapy [18]. In this study, Tph2 − / − and CTR mice were treated with CIT or TIA for 21 days.…”