Nature Research, Nature Neuroscience, 2(17), p. 232-239, 2014
DOI: 10.1038/nn.3615
Full text: Download
While postsynaptic GlyRs as α/β heteromers attract the most research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that DH-CBD, a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing the point-mutations in the α1 GlyRs 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 auditory brainstem are most vulnerable to hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive than heteromers to DH-CBD, suggesting presynaptic GlyRs as a primary target. Consistent with this, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency.