title: 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 (p38α(5HT-)). We found p38α(5HT-) and control (p38α(5HT+)) 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 p38α(5HT-) animals. Moreover, although LPS elevated plasma corticosterone and central/peripheral pro-inflammatory cytokines in p38α(5HT-) 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.
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Baganz
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Lindler
authors.affiliation: Osher Center for Integrative Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Robson
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Deneris
authors.affiliation: Institute for Psychiatric Neuroscience, Nashville, TN, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Hewlett
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Blakely
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D005260:Female; D007107:Immune System / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008636:Mesencephalon / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012701:Serotonin / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D009435:Synaptic Transmission / Q000276:immunology / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000097:blood / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; D012701:Serotonin; D048051:p38 Mitogen-Activated Protein Kinases