Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Nat Neurosci. 2014 Feb;17(2):232-9. doi: 10.1038/nn.3615. Epub 2014 Jan 5.


Although postsynaptic glycine receptors (GlyRs) as αβ heteromers attract considerable research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing point mutations in α1 GlyRs that are responsible for a hereditary startle-hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in the auditory brainstem are more vulnerable than heteromers to hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive to DH-CBD than are heteromers, suggesting presynaptic GlyRs as a primary target. Consistent with this idea, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α1 GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Brain Stem / cytology
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology
  • Female
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / physiology
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism*
  • Receptors, Glycine / genetics
  • Receptors, Glycine / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Spinal Cord / cytology
  • Stiff-Person Syndrome / genetics
  • Stiff-Person Syndrome / pathology
  • Tetrodotoxin / pharmacology
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Excitatory Amino Acid Antagonists
  • Receptors, Glycine
  • Sodium Channel Blockers
  • Tetrodotoxin
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-amino-5-phosphopentanoic acid
  • Valine