Upregulation of Vesicular Glutamate Transporter 2 and STAT3 Activation in the Spinal Cord of Mice Receiving 3,3'-Iminodipropionitrile.
Chronic administration of 3,3'-iminodipropionitrile (IDPN) causes axonal impairment. Although controversy still remains, it has been suggested that IDPN intoxication mimics the axonopathy of amyotrophic lateral sclerosis (ALS). Interestingly, recent studies including our own showed that signal transducer and activator of transcription 3 (STAT3) in spinal α-motoneurons was activated in both IDPN-treated mice and SOD1 G93A mice, a genetic model of familial ALS. Because activation of STAT3 occurs in response to various stimuli, such as axonal injury, ischemia, and excessive glutamate, here we focused on a potential link between phosphorylated STAT3 (pSTAT3, an active form) and vesicular glutamate transporter 2 (VGluT2, a regulator of glutamate storage and release) in IDPN-treated mice and SOD1 G93A mice. Impairment of axonal transport was confirmed by western blot analysis: the expression levels of phosphorylated neurofilament H were elevated in both models. As shown in SOD1 G93A mice, the expression frequencies of VGluT2 in synaptophysin-positive (SYP)+ presynaptic terminals around spinal α-motoneurons were significantly higher in IDPN-treated mice than in vehicle controls. The coverages of spinal α-motoneurons by VGluT2+ presynaptic terminals were more elevated around pSTAT3+ cells than around pSTAT3- cells in IDPN-treated mice and SOD1 G93A mice. Considering that excessive glutamate is shown to be involved in axonal impairment and STAT3 activation, the present results suggest that IDPN-induced upregulation of VGluT2 may result in an increase in glutamate, which might cause axonopathy and induction of pSTAT3. The link between upregulation of VGluT2 and activation of STAT3 via glutamate may represent a common pathological feature of IDPN-treated mice and SOD1 G93A mice.
['Ohgomori|Tomohiro|T|', 'Yamasaki|Ryo|R|', 'Kira|Jun-Ichi|JI|', 'Jinno|Shozo|S|0000-0002-7596-8118']
D000818:Animals D001583:Benzoxazoles D002795:Choline O-Acetyltransferase D027342:Excitatory Amino Acid Transporter 2 D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D009046:Motor Neurons D009419:Nerve Tissue Proteins D009570:Nitriles D017729:Presynaptic Terminals D011806:Quinolinium Compounds D050796:STAT3 Transcription Factor D013116:Spinal Cord D013126:Spinal Nerve Roots D013482:Superoxide Dismutase D016708:Synaptophysin D015854:Up-Regulation D050599:Vesicular Glutamate Transport Protein 2
Vesicular glutamate transporter 2 Amyotrophic lateral sclerosis Signal transducer and activator of transcription 3 3,3′-Iminodipropionitrile SOD1 G93A mouse