| First Author | Baganz NL | Year | 2015 |
| Journal | Transl Psychiatry | Volume | 5 |
| Pages | e671 | PubMed ID | 26529424 |
| Mgi Jnum | J:248695 | Mgi Id | MGI:6093830 |
| Doi | 10.1038/tp.2015.168 | Citation | Baganz NL, et al. (2015) A requirement of serotonergic p38alpha mitogen-activated protein kinase for peripheral immune system activation of CNS serotonin uptake and serotonin-linked behaviors. Transl Psychiatry 5:e671 |
| abstractText | 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)-1beta 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 p38alpha MAPK signaling in LPS/IL-1beta-induced SERT regulation and attendant behavioral responses, we pursued studies in mice that afford conditional elimination of p38alpha MAPK in 5-HT neurons (p38alpha(5HT-)). We found p38alpha(5HT-) and control (p38alpha(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-1beta fails to increase SERT activity in midbrain synaptosomes prepared from p38alpha(5HT-) animals. Moreover, although LPS elevated plasma corticosterone and central/peripheral pro-inflammatory cytokines in p38alpha(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 p38alpha MAPK signaling in 5-HT neurons for the translation of immune activation to SERT regulation and 5-HT-modulated behaviors. |
