title: Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase.
abstract: Evolving evidence suggests that brain inflammation and the buildup of proinflammatory cytokine increases the risk for cognitive decline and cognitive dysfunction. Interleukin-1β (IL-1β), acting via poorly understood mechanisms, appears to be a key cytokine in causing these deleterious effects along with a presumably related loss of long-term potentiation (LTP)-type synaptic plasticity. We hypothesized that IL-1β disrupts brain-derived neurotrophic factor (BDNF) signaling cascades and thereby impairs the formation of filamentous actin (F-actin) in dendritic spines, an event that is essential for the stabilization of LTP. Actin polymerization in spines requires phosphorylation of the filament severing protein cofilin and is modulated by expression of the immediate early gene product Arc. Using rat organotypic hippocampal cultures, we found that IL-1β suppressed BDNF-dependent regulation of Arc and phosphorylation of cofilin and cAMP response element-binding protein (CREB), a transcription factor regulating Arc expression. IL-1β appears to act on BDNF signal transduction by impairing the phosphorylation of insulin receptor substrate 1, a protein that couples activation of the BDNF receptor TrkB to downstream signaling pathways regulating CREB, Arc, and cofilin. IL-1β upregulated p38 mitogen-activated protein kinase (MAPK), and inhibiting p38 MAPK prevented IL-1β from disrupting BDNF signaling. IL-1β also prevented the formation of F-actin in spines and impaired the consolidation, but not the induction, of BDNF-dependent LTP in acute hippocampal slices. The suppressive effect of IL-1β on F-actin and LTP was prevented by inhibiting p38 MAPK. These findings define a new mechanism for the action of IL-1β on LTP and point to a potential therapeutic target to restore synaptic plasticity.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, USA.
authors.forename: Liqi
authors.initials: L
authors.lastname: Tong
authors.forename: G Aleph
authors.initials: GA
authors.lastname: Prieto
authors.forename: Enikö A
authors.initials: EA
authors.lastname: Kramár
authors.forename: Erica D
authors.initials: ED
authors.lastname: Smith
authors.forename: David H
authors.initials: DH
authors.lastname: Cribbs
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D051338:Cofilin 1 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
chemical_list: D000199:Actins; D019208:Brain-Derived Neurotrophic Factor; C495812:Cfl1 protein, rat; D051338:Cofilin 1; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases