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.
Highlights
IntroductionDepression remains the leading cause of disability worldwide.[1] the etiology of depression and other mood disorders is complex, multiple studies have reported that depressed subjects display an elevation of pro-inflammatory cytokines (see Raison et al.[2] for review)
Depression remains the leading cause of disability worldwide.[1] the etiology of depression and other mood disorders is complex, multiple studies have reported that depressed subjects display an elevation of pro-inflammatory cytokines
The P-p38 MAPK antibody we used does not discriminate among p38 MAPK isoforms; as noted earlier, prior pharmacological, viral and short interfering RNA manipulations support an involvement of p38α MAPK in sensitive 5-HT transporter (SERT) regulation.[17,18,20,33,34]
Summary
Depression remains the leading cause of disability worldwide.[1] the etiology of depression and other mood disorders is complex, multiple studies have reported that depressed subjects display an elevation of pro-inflammatory cytokines (see Raison et al.[2] for review). Bacterial mimetics such as poly I:C and lipopolysaccharide (LPS), result in mood alterations in humans.[3] We4 and others[2,3,5] have hypothesized that inappropriate activation of immune signaling mechanisms may contribute to risk for mood disorders in the absence of environmental triggers. Significant evidence points to a bidirectional interaction between the immune system and serotonin (5-hydroxytryptamine, 5-HT) signaling in both the brain and periphery.[2,6] Peripheral immune system stimulation and/or inflammatory cytokines have been found to modulate 5-HT neuron activation, 5-HT synthesis and 5-HT release, and alter levels and/or signaling of various 5-HT receptor subtypes.[7,8,9,10,11,12,13,14,15,16]
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