Microglia support ATF3-positive neurons following hypoglossal nerve axotomy. (September 2017)

• Record Type: Journal Article
• Authors: Tanaka, Tatsuhide; Murakami, Koichi; Bando, Yoshio; Nomura, Taichi; Isonishi, Ayami; Morita-Takemura, Shoko; Tatsumi, Kouko; Wanaka, Akio; Yoshida, Shigetaka
• Is Part Of: Neurochemistry international. Volume 108(2017)
• Page Start: 332
• Page End: 342
• Publication Date: 2017-09
• Subjects: Peripheral nerve injury -- Minocycline -- CNTF -- Colchicine; ATF3 Activating transcription factor 3 -- ALS Amyotrophic lateral sclerosis -- BDNF Brain derived neurotrophic factor -- CNTF Ciliary neurotrophic factor -- CNS Central nervous system -- ChAT Choline acetyltransferase -- GAP43 Growth associated protein 43 -- GAPDH Glyceraldehyde-3-phosphate dehydrogenase -- G-CSF Granulocyte colony stimulating factor -- GDNF Glial cell line-derived neurotrophic factor -- IL-1β Interleukin-1β -- JAK Janus kinase -- LDH Lactate dehydrogenase -- LIF Leukemia inhibitory factor -- NGF Nerve growth factor -- PB Phosphate buffer -- PBS Phosphate buffered saline -- PCR Polymerase chain reaction -- SDS-PAGE Sodium dodecyl sulfate poly-acrylamide gel electrophoresis -- SOD Superoxide dismutase -- STAT3 Signal transducer and activator of transcription 3 -- TNF-α Tumor necrosis factor-α; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2017.05.007
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Microglia are essential in developmental processes and maintenance of neuronal homeostasis. Experimental axotomy of motor neurons results in neurodegeneration, and microglia in motor nuclei become activated and migrate towards injured neurons. However, whether these activated microglia are protective or destructive to neurons remains controversial. In the present study, we transected the hypoglossal nerve in BALB/c mice, causing activating transcription factor 3 (ATF3) and growth associated protein 43 (GAP43) induction, and partial neuronal death. Inhibition of microglial accumulation by minocycline administration impaired microglial accumulation, decreased GAP43 mRNA expression, and reduced motor neuron survival. Expression of ATF3 contributed to nerve regeneration, and increased within 6 h after axotomy, prior to microglial migration. Further, microglial contact with neuronal cell bodies was associated with neuronal ATF3 expression. Colchicine administration blocked lesion-induced ATF3 transcription in axotomized neurons and microglial accumulation. In addition, perineuronal microglia-derived ciliary neurotrophic factor (CNTF) increased, indicating that perineuronal microglia in the hypoglossal nucleus protect axotomized motor neurons by releasing trophic factors. We also observed that microglia secrete CNTF and that neurons have CNTFRα and can respond to it in vitro . CNTF promote neurite elongation and neuronal survival of primary cultured neurons. Microglia make contact through unknown neuronal signals that are possibly regulated by ATF3 in hypoglossal nucleus. Moreover, they play important roles in regenerating motor neurons and are potential new therapeutic targets for motor neuron diseases. Highlights: Injury signals from the severed stump induce ATF3 expression in injured neurons, and attract microglia to the hypoglossal nucleus and neuronal cell bodies. Minocycline administration during the microglial accumulation period reduces the number of surviving neurons. Minocycline reduces GAP43 mRNA expression during early regeneration. Perineuronal microglia in the hypoglossal nucleus express the neurotrophic factor, CNTF.