Peripheral Serotonin Deficiency Affects Anxiety-like Behavior and the Molecular Response to an Acute Challenge in Rats.

Serotonin is synthetized through the action of tryptophan hydroxylase (TPH) enzymes. While the TPH2 isoform is responsible for the production of serotonin in the brain, TPH1 is expressed in peripheral organs. Interestingly, despite its peripheral localization, alterations of the gene coding for TPH1 have been related to stress sensitivity and an increased susceptibility for psychiatric pathologies. On these bases, we took advantage of newly generated TPH1-/- rats, and we evaluated the impact of the lack of peripheral serotonin on the behavior and expression of brain plasticity-related genes under basal conditions and in response to stress. At a behavioral level, TPH1-/- rats displayed reduced anxiety-like behavior. Moreover, we found that neuronal activation, quantified by the expression of Bdnf and the immediate early gene Arc and transcription of glucocorticoid responsive genes after 1 h of acute restraint stress, was blunted in TPH1-/- rats in comparison to TPH1+/+ animals. Overall, we provided evidence for the influence of peripheral serotonin levels in modulating brain functions under basal and dynamic situations.

Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link.

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other's impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

Offspring's own serotonin transporter genotype, independently from the maternal one, increases anxiety- and depression-like behavior and alters neuroplasticity markers in rats.

INTRODUCTION: Developmental changes due to early life variations in the serotonin system affect stress-related behavior and neuroplasticity in adulthood. These outcomes can be caused both by offspring's own and maternal serotonergic genotype. We aimed to dissociate the contribution of the own genotype from the influences of mother genotype. METHODS: Sixty-six male homozygous (5-HTT-/-) and heterozygous (5-HTT+/-) serotonin transporter knockout and wild-type rats from constant 5-HTT genotype mothers crossed with varying 5-HTT genotype fathers were subjected to tests assessing anxiety- and depression-like behaviors. Additionally, we measured plasma corticosterone levels and mRNA levels of BDNF, GABA system and HPA-axis components in the prelimbic and infralimbic cortex. Finally, we assessed the effect of paternal 5-HTT genotype on these measurements in 5-HTT+/- offspring receiving their knockout allele from their mother or father. RESULTS: 5-HTT-/- offspring exhibited increased anxiety- and depression-like behavior in the elevated plus maze and sucrose preference test. Furthermore, Bdnf isoform VI expression was reduced in the prelimbic cortex. Bdnf isoform IV and GABA related gene expression was also altered but did not survive false discovery rate (FDR) correction. Finally, 5-HTT+/- offspring from 5-HTT-/- fathers displayed higher levels of anxiety- and depression-like behavior and changes in GABA, BDNF and HPA-axis related gene expression not surviving FDR correction. LIMITATIONS: Only male offspring was tested. CONCLUSIONS: Offspring's own 5-HTT genotype influences stress-related behaviors and Bdnf isoform VI expression, independently of maternal 5-HTT genotype. Paternal 5-HTT genotype separately influenced these outcomes. These findings advance our understanding of the 5-HTT genotype dependent susceptibility to stress-related disorders.

Maternal serotonin transporter genotype and offsprings' clinical and cognitive measures of ADHD and ASD.

Serotonin (5-HT) is an important factor for prenatal neurodevelopment whereby its neurotrophic actions can be regulated through maternal-fetal interactions. We explored if maternal 5-HTTLPR genotype is associated with clinical and cognitive measures of attention-deficit/hyperactivity disorder (ADHD) and comorbid autism spectrum disorder (ASD) in typically-developing and ADHD-diagnosed offspring, beyond classical inheritance and environmental- and comorbidity-mediators/confounders. Family-based variance decomposition analyses were performed incorporating 6-31 year-old offsprings' as well as parental genotypes of 462 ADHD and control families from the NeuroIMAGE cohort. Dependent measures were offsprings' ADHD symptom- and ASD trait-scores and cognitive measures including executive functioning (including response inhibition and cognitive flexibility), sustained attention, reward processing, motor control, and emotion recognition. Offsprings' stereotyped behavior was predicted by an interaction between maternal 5-HTTLPR genotype and offsprings' sex. Furthermore, offspring of mothers with low-expressing genotypes demonstrated larger reward-related reductions in reaction time. While specifically adult male offspring of these mothers reported a faster reversal learning with less errors, specifically young female offspring of these mothers were more accurate in identifying happy faces. Adult offspring from the mothers with low-expressing 5-HTTLPR genotypes were also slower in identifying happy faces. However, this association seemed to be mediated by offsprings' high anxiety levels. In sum, we found some support for a role of the maternal 5-HT system in modulating fetal brain development and behavior. Offsprings' cognitive measures might be more sensitive to small alterations within the maternal 5-HT system than their ADHD and ASD clinical phenotypes. Further studies are needed to specify the association between maternal genotype and risk for neurodevelopmental disorders.

Neurodevelopmental and behavioral consequences of perinatal exposure to the HIV drug efavirenz in a rodent model.

Efavirenz is recommended as a preferred first-line drug for women of childbearing potential living with human immunodeficiency virus. Efavirenz is known for its central nervous system side effects, which are partly mediated by serotonergic actions. The neurotransmitter serotonin exerts neurotrophic effects during neurodevelopment and antenatal exposure to serotonergic agents has been linked to developmental delay. Although the teratogenic risks of efavirenz appear to be minimal, data on long-term developmental effects remain scarce. Here, we aimed to investigate the short- and long-term behavioral and neurodevelopmental effects of perinatal efavirenz exposure. We treated pregnant rats from gestation day 1 until postnatal day 7 with efavirenz (100 mg/kg) or vehicle. We measured behavioral outcomes in male offspring during the first 3 postnatal weeks, adolescence and adulthood, and conducted brain immunohistochemistry analyses after sacrifice. Perinatal efavirenz exposure resulted in reduced body weight and delayed reflex and motor development. During adulthood, we observed a decrease in the total number of cells and mature neurons in the motor cortex, as well as an increase in the number of Caspase-3-positive cells and serotonergic fibers. Together, our data show a developmental delay and persistent changes in the brain motor cortex of rats exposed to efavirenz perinatally. Because over 1 million children born annually are exposed to antiretroviral therapy, our findings underline the need for clinical studies on long-term neurodevelopmental outcomes of perinatal exposure to efavirenz.