title: Menin regulates spinal glutamate-GABA balance through GAD65 contributing to neuropathic pain.
abstract: BACKGROUND
  Our previous work found that tumor suppressor menin potentiates spinal synaptic plasticity in the context of peripheral nerve injury-induced neuropathic hypersensitivity, but the underlying molecular mechanisms are not clear. We hereby assessed the role of menin in regulating the spinal balance between glutamate and GABA and its contribution to the pathological condition of nerve injury-induced hypersensitivity.
  
  
  METHODS
  In spared nerve injury induced C57BL/6 mice, mechanical withdrawal threshold was measured with von Frey filaments after intrathecal administration of small interfering RNA (siRNA) of MEN1 or/and subcutaneous histone deacetylase (HDAC) inhibitors to control the level of glutamic acid decarboxylase 65 (GAD65). Immunoblotting and high-performance liquid chromatography were used to detect the level of protein expression and spinal glutamate and GABA, respectively.
  
  
  RESULTS
  Genetic knockdown of spinal menin alleviated nerve injury evoked mechanical hypersensitivity, which was strongly associated with the alteration of the spinal level of GAD65 that resulted in an imbalance of glutamate/GABA ratio from the baseline ratio of 5.8 ± 0.9 (×10(-4)) to the peak value of 58.6 ± 11.8 (×10(-4)) at the day 14 after SNI (p < 0.001), which was reversed by MEN1 siRNA to 14.7 ± 2.1 (×10(-4)) at the day 14 after nerve injury (p < 0.01). In further, selective inhibitors of HDACs considerably reversed the ratio of spinal glutamate and GABA, and also alleviated the mechanical withdrawal threshold markedly.
  
  
  CONCLUSIONS
  Our findings provide mechanistic insight into the contribution of the upregulated spinal menin to peripheral nerve injury induced neuropathic hypersensitivity by regulating glutamate-GABA balance through deactivating GAD65.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Shiqin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wu
authors.affiliation: The Institute of Pediatrics, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xirong
authors.initials: X
authors.lastname: Guo
authors.affiliation: The Institute of Pediatrics, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China; Division of Neuroscience, Bonoi Academy of Science & Education, Winston-Salem, NC, USA. Electronic address: zfwang50@njmu.edu.cn.
authors.forename: Fuzhou
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D005968:Glutamate Decarboxylase / Q000502:physiology*; D018698:Glutamic Acid / Q000032:analysis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000209:etiology*; D059348:Peripheral Nerve Injuries / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000737:chemistry*; D005680:gamma-Aminobutyric Acid / Q000032:analysis*
chemical_list: C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: Epigenetics; Menin; Neuropathic pain; Neurotransmitter; Spinal cord