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MEF2C Mediates Chronic Pain in Rodent Neuropathy Models
Author(s) -
Serafini Randal Alexander,
Sakloth Farhana,
Pryce Kerri,
Bertherat Feodora,
Akbarian Schahram,
Zachariou Venetia
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02107
Subject(s) - mef2c , neuropathic pain , neuroscience , chronic pain , medicine , nerve injury , mef2 , transcription factor , psychology , biology , enhancer , genetics , gene
Peripheral nerve injury triggers a number of maladaptive changes in both peripheral and central sites, leading to debilitating hypersensitivity, as well as cognitive, motivational, and affective deficits. Understanding the epigenetic and transcriptional events mediating pathological pain and synaptic reorganization will provide essential information for novel approaches towards the management of neuropathic pain. Our lab has previously demonstrated that prolonged peripheral nerve injury leads to an upregulation of histone deacetylase 5 (HDAC5) in the mouse Nucleus Accumbens (NAc), and revealed a dynamic role of HDAC5 in the antiallodynic efficacy of monoamine‐targeting antidepressants. HDAC5 negatively regulates the expression of Myocyte Enhancer Factor 2C (MEF2C), a transcription factor critical for synaptic plasticity in adulthood. Aberrant MEF2C expression contributes to clinical neuropsychiatric abnormalities such as autism and schizophrenia. By utilizing qPCR and RNAscope in situ hybridization, we found that long‐term peripheral nerve injury dynamically affects MEF2C expression in distinct cellular populations of chronic pain circuits. We also used adeno‐associated vectors to overexpress MEF2C in the NAc of adult mice in order to determine the impact of this transcription factor in the trajectory of sensory hypersensitivity associated with peripheral nerve injury. We found that while MEF2C overexpression did not affect the induction of sensory hypersensitivity, it did disrupt the maintenance of sensory hypersensitivity symptoms. Specifically, MEF2C over‐expressors recover from mechanical allodynia and show restored motivational drive. In conclusion, our findings suggest that manipulation of the plasticity‐mediating transcription factor, MEF2C, in the brain reward system holds promise for interrupting the chronification of pain, as well as its affective components. We are further investigating the mechanisms underlying neuropathy‐related changes in MEF2C expression and/or activity via phosphorylation‐specific protein analysis, in vivo DNA methyltransferase identification (DamID), and gene silencing tools for downstream molecular targets. Support or Funding Information NS086444 & NS111351 NINDS,MSTP T32 NIH T32 GM007280,Irene & Eric Simon Brain Research Foundation Fellowship