A requirement of serotonergic p38α mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors

Abstract

Alterations in central serotonin (5-hydroxytryptamine, 5-HT) neurotransmission and peripheral immune activation have been linked to multiple neuropsychiatric disorders, including depression, schizophrenia and autism. The antidepressant-sensitive 5-HT transporter (SERT, SLC6A4), a critical determinant of synaptic 5-HT inactivation, can be regulated by pro-inflammatory cytokine signaling. Systemic innate immune system activation via intraperitoneal lipopolysaccharide (LPS) injection rapidly elevates brain SERT activity and 5-HT clearance. Moreover, the pro-inflammatory cytokine interleukin (IL)-1β rapidly stimulates SERT activity in raphe nerve terminal preparations ex vivo, effects that are attenuated by pharmacological p38 MAPK inhibition. To establish a role of serotonergic p38α MAPK signaling in LPS/IL-1β-induced SERT regulation and attendant behavioral responses, we pursued studies in mice that afford conditional elimination of p38α MAPK in 5-HT neurons (p38α5HT−). We found p38α5HT− and control (p38α5HT+) littermates to be indistinguishable in viability and growth and to express equivalent levels of SERT protein and synaptosomal 5-HT transport activity. Consistent with pharmacological studies, however, IL-1β fails to increase SERT activity in midbrain synaptosomes prepared from p38α5HT− animals. Moreover, although LPS elevated plasma corticosterone and central/peripheral pro-inflammatory cytokines in p38α5HT− animals, elevations in midbrain SERT activity were absent nor were changes in depressive and anxiety-like behaviors observed. Our studies support an obligate role of p38α MAPK signaling in 5-HT neurons for the translation of immune activation to SERT regulation and 5-HT-modulated behaviors.

Neuronal MAP kinase p38α inhibits c-Jun N-terminal kinase to modulate anxiety-related behaviour

“…Previous studies have reported the effects of conditional deletion of p38α in the CNS, specifically targeting dopaminergic 15 or serotonergic neurons 21 . To address outcomes of pan-neuronal deficiency of p38α, we crossed p38α floxed ( p38α lox ) mice 22 with mice that express cre recombinase under control of the pan-neuronal murine Thy1.2 promoter 23 .…”

Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery

“…While the primary focus of this review is depressive behaviors, there is a growing literature demonstrating inflammation-induced increases in anxiety-like behaviors in rodents ( Salazar et al, 2012 ; Bassi et al, 2012 ; Gibney et al, 2013 ; Baganz et al, 2015 ; Savignac et al, 2016 ; Sriram et al, 2016 ; Sulakhaiya et al, 2016 ) and humans ( Grigoliet et al, 2011 ; Reichenberg et al, 2001 ; Lasselin et al, 2016 ). Sulakhaiya (2016) found that LPS-treated animals have an increase in anxiety-like behavior, as measured by the elevated plus maze.…”

“…It is also important to mention that mechanisms other than the kynurenine metabolites are being investigated in the inflammation-induced depression model, including brain derived neurotrophic factor ( Zhang et al, 2014 ), leptin ( Kurosawa et al, 2015 ), glucocorticoids ( Adzic et al, 2015 ), and alterations in neurotransmitters, such as adrenaline/noradrenaline (Sekio and Seki et al, 2014 ; Zhu et al, 2015 ), dopamine ( Yeh et al, 2015 ), and acetylcholine ( Ming et al, 2015 ).…”

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Finally, several behavioral effects that attend peripheral LPS administration (immobility in the tail suspension and forced swim tests) were absent in lost in both IL-1R and SERT KO mice or with SB203580 injections, suggesting that inflammatory regulation of SERT via p38 MAPK pathways may induce depression-like behavior. In this regard, Baganz et al (2015) recently demonstrated that p38a MAPK is required in 5-HT neurons to support both activation of brain SERT and anxiety and depression-like behaviors after an intraperitoneal LPS injection. These studies provide definitive evidence that the a isoform of p38 MAPK is engaged in SERT regulation by immune stimuli in vivo and identify mechanisms by which peripheral inflammatory insults can change behavior through alterations in 5-HT signaling (see also Baganz and Blakely, 2013).…”