Activated p38 MAPK is associated with decreased CSF 5-HIAA and increased maternal rejection during infancy in rhesus monkeys

Abstract

These data accord with earlier studies demonstrating regulation of RGS4 expression by dopamine 4 and specifically by COMT genotype. 8 Lipska and colleagues showed significantly decreased RGS4 mRNA expression in the DLPFC of Val/Val subjects, relative to Met-carriers. These changes suggest that variation in cortical dopamine may alter RGS4-dependent signaling by regulating its transcription. Alternatively or in addition, genetic variation in RGS4 may become more manifest in COMT Val/Val subjects, whose cortical synaptic dopamine levels are lower. Our findings support earlier statistical genetic and neuropathological evidence for epistasis between COMT and RGS4 by demonstrating an interaction between these two putative risk genes on an in vivo measure of prefrontal function. These results bolster the notion that COMT val158met genetic background mediates the impact of other schizophrenia susceptibility genes. Recent data indicate that activation of the p38 mitogen-activated protein kinase (MAPK) signaling cascade by cytokines including interleukin (IL)-1 and tumor necrosis factor (TNF)-a increases the expression and activity of the serotonin transporter (SERT). Herein, we report that increased p38 activity, as manifested by an increased percentage of peripheral blood monocytes staining positive for intracellular phosphorylated p38 (p-p38), was associated with decreased cerebrospinal fluid (CSF) concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and increased maternal rejection in 17 rhesus monkeys, 8 of whom were exposed to poor maternal care as infants. These data provide the first evidence of an in vivo relationship between p38 MAPK activation and brain serotonin metabolism in an animal model of early life stress and indicate that activation of p38 MAPK signaling pathways may participate in the contribution of early life stress to psychiatric morbidity. Early life stress including physical/sexual abuse as well as neglect has been associated with a number of adverse health outcomes including increased anxiety and depression. 1 We recently reported that adolescent rhesus monkeys (Macaca mulatta) exposed to physical abuse and high levels of maternal rejection as infants exhibit increased distress and anxiety, delayed social development and reduced exploration, compared to non-abused animals. 2,3 This early exposure to poor maternal care was also associated with reduced brain serotonergic function as reflected by decreased CSF concentrations of serotonin (5-HT) and the serotonin metabolite, 5-HIAA, that were in turn correlated with increased anxiety-like behavior during adolescence. 4 Data indicate that stress, including early life stress, also can be associated with activation of innate immune responses including release of proinflammatory cytokines and activation of proinflammatory cytokine signaling cascades. 5,6 Relevant to the impact of early life stress on serotonin metabolism, the cytokine signaling pathway, p38 MAPK, has been found to increase expression and activity of the SERT...

Childhood Maltreatment and Coping in Bipolar Disorder

“…maternal isolation/separation or isolation rearing) show that the mPFC is particularly affected by early life emotional stress [55][56][57][58][59][60]. In line, patients and healthy controls reporting CEM show a reduction in dorsal mPFC volume [61][62][63], and dorsal mPFC hypo-activity during higher order cognitive processing [unpublished data].…”

Non-Human Primates: Model Animals for Developmental Psychopathology

“…Evidence of persistent changes in brain systems including reduced corticospinal fluid 5HIAA (5-hydroxy-indoleacetic acid) levels well after weaning suggest that primate maternal abuse might offer some important insights about subsequent risk for pathology in affected offspring (Maestripieri et al, 2006;Sanchez et al, 2007). This approach, however, suffers from the difficulties of operationally defining or quantifying both severity and the critical timing of abuse (Carroll and Maestripieri, 1998).…”

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

“…Increased p38 MAPK activation (phosphorylation) in lymphocytes following the initial injection of IFN-alpha has predicted IFN-alpha-induced depression and fatigue in HCV+ patients (Felger et al, 2011). Furthermore, p38 MAPK activation in peripheral blood monocytes have been shown to be related to decreased CSF concentrations of 5-HIAA in rhesus monkeys exposed to early maternal neglect and abuse (Sanchez et al, 2007). Interestingly, acute administration of cytokines, including IFN-gamma, IL-1beta, TNF-alpha (Clement et al, 1997) and IL-6 (Zhang et al, 2001), increase 5-HT release in several brain regions, effects that could be mediated by increased 5-HTT activity in addition to the previously mentioned cytokine-induced changes in 5-HT metabolism.…”