Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

Abstract

Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism.

Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region- and sex-specific manner in the adult mouse brain

“…To demonstrate region specificity of arsenic toxicity for the dentate gyrus, we assessed histone modifications in the frontal cortex of both males and females. Additionally, the frontal cortex has been implicated in the pathophysiology of depression, and we have previously shown our model of arsenic exposure induces depressive-like behaviors in adulthood (Martinez et al, 2008, Tyler et al, 2014). Thus, in the male frontal cortex, we observed increased levels of both H3K4me3 and associated MLL, similar to the pattern observed in the male dentate gyrus, though KDM5B protein expression was only slightly decreased.…”

“…C57BL/6 mice obtained from Jackson Labs were maintained on a reverse light/dark cycle (lights off at 0800) with ad libitum access to food and water in the Animal Resource Facility at UNM. Arsenic exposure was performed as previously described (Tyler et al, 2014), as depicted in Figure 1. Briefly, singly-housed female mice aged 55 days were acclimated to drinking 50 parts-per-billion arsenic water (sodium arsenate, Sigma Aldrich) for 10 days prior to mating.…”

“…Immunoblotting for chromatin-modifying proteins was conducted essentially as previously described using our established protocols (Goggin et al, 2012, Tyler et al, 2014). Dentate gyrus or frontal cortex tissue lysates from one animal were prepared, and the nuclear fraction was isolated for protein expression analysis.…”

“…Of the several HMTs that impart three methyl groups on H3K4, mixed lineage leukemia factor (MLL1) is of particular interest as it is essential to proper neurogenesis (Lim et al, 2009), and we have demonstrated that our DAE paradigm inhibits adult hippocampal neurogenesis in the dentate gyrus (Tyler and Allan, 2013, Tyler et al, 2014). Additionally, the impact of arsenic on MLL expression has not been measured to date.…”

“…Using a perinatal exposure paradigm to 50 ppb sodium arsenate through all three trimesters of fetal/neonatal development, we have previously demonstrated that arsenic reduces adult hippocampal neurogenesis, particularly differentiation of neural progenitor cells, leading to greater susceptibility to developing stress-induced depressive-like symptoms in adult male mice (Tyler and Allan, 2013, Tyler et al, 2014). Adult neurogenesis is comprised of several processes that include the continual mitotic activity of dentate gyrus neural progenitor cells and their subsequent maturation and integration into the hippocampal circuitry (Ming and Song, 2005).…”