Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to psychiatric disorders

Abstract

Mental disorders including depression and anxiety are continuously rising their prevalence across the globe. Early-life experience of individuals emerges as a main risk factor contributing to the developmental vulnerability to psychiatric disorders. That is, perturbing environmental conditions during neurodevelopmental stages can have detrimental effects on adult mood and emotional responses. However, the possible maladaptive neural mechanisms contributing to such psychopathological phenomenon still remain poorly understood. In this review, we explore preclinical rodent models of developmental vulnerability to psychiatric disorders, focusing on the impact of early-life environmental perturbations on behavioral aspects relevant to stress-related and psychiatric disorders. We limit our analysis to well-established models in which alterations in the serotonin (5-HT) system appear to have a crucial role in the pathophysiological mechanisms. We analyze long-term behavioral outcomes produced by early-life exposures to stress and psychotropic drugs such as the selective 5-HT reuptake inhibitor (SSRI) antidepressants or the anticonvulsant valproic acid (VPA). We perform a comparative analysis, identifying differences and commonalities in the behavioral effects produced in these models. Furthermore, this review discusses recent advances on neurodevelopmental substrates engaged in these behavioral effects, emphasizing the possible existence of maladaptive mechanisms that could be shared by the different models.

Fig. 1. Schematic overview of some of the main effects reported after either stress, SSRI or VPA exposures during gestation and/or early postnatal life, on different brain regions and neurodevelopmental processes.

Different rodent models of exposure to stress (forced swim, helplessness, social defeat, restraint, maternal separation) and to chemical substances (SSRIs, VPA) are shown. Main brain regions affected in these models are indicated (Olfactory bulb OB, Prefrontal cortex PFC, Lateral habenula LHb, Amygdala AMY, Hippocampus HIP, Ventral tegmental area VTA, Dorsal raphe nucleus DRN, Cerebellum CBL), together with summarized effects on neurodevelopmental molecular, cellular, and circuit mechanisms. These include hyperexcitability of glutamate neurons, exuberant glutamate synaptogenesis, decreases in dendrite and spine remodeling, decreased neurogenesis, reduction of the balance of glutamate/GABA transmission, reduced gliogenesis and myelination, and multiple changes in epigenetic control of gene expression.