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Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease.

Research paper by Wei W Xiong, Shao-Rui SR Chen, Liming L He, Kejun K Cheng, Yi-Lin YL Zhao, Hong H Chen, De-Pei DP Li, Gregg E GE Homanics, John J Peever, Kenner C KC Rice, Ling-gang LG Wu, Hui-Lin HL Pan, Li L Zhang

Indexed on: 07 Jan '14Published on: 07 Jan '14Published in: Nature Neuroscience



Abstract

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.