A requirement of serotonergic p38 alpha mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors

作者：Baganz N L; Lindler K M; Zhu C B; Smith J T; Robson M J; Iwamoto H; Deneris E S; Hewlett W A; Blakely R D

来源：Translational Psychiatry, 2015, 5(11): e671.

DOI：10.1038/tp.2015.168

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)-1 beta 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 p38 alpha MAPK signaling in LPS/IL-1 beta-induced SERT regulation and attendant behavioral responses, we pursued studies in mice that afford conditional elimination of p38 alpha MAPK in 5-HT neurons (p38 alpha(5HT-)). We found p38 alpha(5HT-) and control (p38 alpha(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-1 beta fails to increase SERT activity in midbrain synaptosomes prepared from p38 alpha(5HT-) animals. Moreover, although LPS elevated plasma corticosterone and central/peripheral pro-inflammatory cytokines in p38 alpha(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 p38 alpha MAPK signaling in 5-HT neurons for the translation of immune activation to SERT regulation and 5-HT-modulated behaviors.

• 出版日期2015-11-3