title: Regulated neuronal neuromodulation via spinal cord expression of the gene for the inwardly rectifying potassium channel 2.1 (Kir2.1).
abstract: BACKGROUND
  Neuromodulation is used to restore neural function in disorders that stem from an imbalance in the activity of specific neural networks when they prove refractory to pharmacological therapy. The Kir2.1 gene contributes to stabilizing the resting potential below the threshold of activation of voltage-gated sodium channels and action potentials. Therefore, the delivery of the Kir2.1 gene to neuronal cells could reduce the probability of action potential generation, inhibiting excessive neural activity.
  
  
  OBJECTIVE
  To address the hypothesis that overexpression of the inwardly rectifying potassium channel 2.1 (Kir2.1) gene could inhibit motor neuron activity and therefore be therapeutically used in gene-based neuromodulation.
  
  
  METHODS
  To induce expression of Kir2.1, the inducible RheoSwitch promoter was used and controlled by ligand. In vivo gene expression was accomplished by an adenoviral vector to deliver unilaterally into the lumbar spinal cord of rats.
  
  
  RESULTS
  Behavioral assays demonstrated that neuromuscular inhibition was exclusive to rats that received the ligand. Histological analysis also showed evidence of some motor neuron loss in these animals. Behavioral effects of Kir2.1 expression were completely reversible, arguing that the behavioral effect did not result from motor neuron death.
  
  
  CONCLUSIONS
  Delivery of the gene for Kir2.1 inhibits neurons by resisting depolarization to the action potential threshold. Regulated neuronal expression of Kir2.1 may provide an elegant means for neuromodulation in a selected neuronal population.
authors.affiliation: Emory University, Department of Neurosurgery, Atlanta, GA 30322, USA. nboulis@emory.edu
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Boulis
authors.forename: Chalonda R
authors.initials: CR
authors.lastname: Handy
authors.forename: Christina A
authors.initials: CA
authors.lastname: Krudy
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Donnelly
authors.forename: Thais
authors.initials: T
authors.lastname: Federici
authors.forename: Colin K
authors.initials: CK
authors.lastname: Franz
authors.forename: Emily M
authors.initials: EM
authors.lastname: Barrow
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Teng
authors.forename: Prasanna
authors.initials: P
authors.lastname: Kumar
authors.forename: Dean
authors.initials: D
authors.lastname: Cress
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology*
chemical_list: C489457:KCNJ2 protein, human; D009467:Neuromuscular Depolarizing Agents; D024661:Potassium Channels, Inwardly Rectifying