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Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Nature Neuroscience volume 17, pages 232–239 (2014)Cite this article

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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.

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Figure 1: The α1R271Q mutation impairs GlyR function and causes exaggerated startle behavior in mice.
Figure 2: DH-CBD rescues α1 R271Q mutation–induced GlyR deficiency and hyper-reflexia in mice.
Figure 3: Site-specific restoration of hyperekplexic GlyR dysfunction and startle responses by DH-CBD.
Figure 4: Differential sensitivity of homomeric and heteromeric GlyRs to hyperekplexic mutations and DH-CBD.
Figure 5: Rescue by DH-CBD of diminished glycine release in spinal slices from α1 R271Q mutant mice.
Figure 6: Differential sensitivity of presynaptic and postsynaptic GlyRs to hyperekplexic mutation and rescue by DH-CBD.

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Acknowledgements

We thank A. Harris and Y. Blednov (University of Texas at Austin) for providing the α1 Q266I, α1 S267Q and α1 M287L mutant mice. We thank D.M. Lovinger for instrumental support and comments on the manuscript. This work was supported by funds from the intramural programs of the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse and US National Institutes of Health grants to G.E.H. (AA10422) and from the National Institute of Neurological Disorders and Stroke to H.-L.P. (NS045602 and NS073935).

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Authors and Affiliations

  1. Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA

    Wei Xiong & Li Zhang

  2. School of Life Sciences, University of Science and Technology of China, Hefei, China.,

    Wei Xiong

  3. Department of Anesthesiology and Perioperative Medicine, Center for Neuroscience and Pain Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Shao-Rui Chen, Yi-Lin Zhao, Hong Chen, De-Pei Li, Kenner C Rice & Hui-Lin Pan

  4. Synaptic Transmission Section, National Institute of Neurological and Stroke Disorders, National Institutes of Health, Bethesda, Maryland, USA

    Liming He & Ling-gang Wu

  5. Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA

    Kejun Cheng

  6. Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Gregg E Homanics

  7. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Gregg E Homanics

  8. Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada

    John Peever

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Contributions

W.X. and L.Z. conducted mutagenesis and animal behavioral tests. W.X. conducted patch-clamp recordings in HEK-293 cells. S.-R.C., Y.-L.Z., H.C., D.-P.L. and H.-L.P. conducted spinal slice recordings. L.H., W.X. and L.W. conducted brain stem calyceal recording. K.C. and K.C.R. synthesized DH-CBD. G.E.H. constructed genetically engineered mouse lines. J.P. provided the transgenic R271Q mouse line. W.X. and H.-L.P. participated in the study design and manuscript writing. L.Z. initiated, designed and supervised the project and wrote the manuscript.

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Correspondence to Li Zhang.

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Integrated supplementary information

Supplementary Figure 1 The R271Q heterozygous mutant mice exhibit a rotarod performance similar to their wild type (WT) littermates.

The data representing the fall time of the R271Q mutant mice (solid squares, n=10) and WT littermates (open squares, n=10) in accelerating mode of rotorod test. All mice received 3 consecutive trials with 10 min intervals each day for three consecutive days. The experiments were carried out in a quiet and isolated room. These mice were handled gently.

Supplementary Figure 2 The efficacy of DH-CBD potentiation of R271Q mutant GlyRs.

Trace records of IGly before and after DH-CBD in HEK-293 cells expressing the α1R271Q mutant GlyRs. Concentration-response curve of DH-CBD potentiation of IGly. The EC50 value of DH-CBD potentiation is 5.7 ± 1.2 μM. Each data point represents mean±s.e. from at least 7 cells. The error bars invisible are smaller than the size of symbols.

Supplementary Figure 3 DH-CBD does not significantly alter strychnine inhibition of GlyRs.

(a). Gly concentration-response curves in the absence and presence of strychnine in HEK-293 cells expressing α1GlyRs. Strychnine at 0.1 μM produced in parallel a right shift of Gly concentration-response curve, respectively. The EC50 values are 56±8 μM for vehicle control (black squares, n=9) and 366±74 μM for strychnine treatment (blue squares, n=7). These values are significantly different (unpaired test, p=0.0023). ; DH-CBD did not significantly alter strychnine inhibition of the agonist binding affinity of α1GlyRs (red squares, n=7, Gly EC50: 368±84 μM. strychnine VS strychnine+DH-CBD , p=0.92) (b) Strychnine (n=6, 1 mg/kg, i.p.) produced exaggerated startle response to acoustic stimulation in C57/BL6 mice (p=0.006, two-way ANOVA). Preadministration of DH-CBD (n=6, 50 mg/kg, i.p.) did not reverse strychnine-induced exaggerated acoustic startle response (p=0.88, two-way ANOVA).

Supplementary Figure 4 Addition of the β subunit does not alter protein expression of R271Q and WT receptors at the cell surfaces

(a) Imaging of Western blot of total and surface proteins of GlyRs expressed in HEK-293 cells using the anti-α1 GlyR and anti-β-actin antiserums. (b) Quantitative analysis of the Western blot of GlyR proteins. Each bar represents mean±s.e. from separate 3 blots. (c) Full gel of surface GlyRs. (d) Full gel of total GlyRs. (e) Full gel of β-actin.

Supplementary Figure 5 DH-CBD does not restore diminished glycinergic transmission in spinal slices from the α1Q266I mutant mice.

(a) Trace records of Gly sIPSC in spinal slices from the WT and α1Q266I mutant mice with and without sustained perfusion of DH-CBD (20 μM) for 6 min. (b) The average frequency and amplitude of Gly sIPSC in spinal slices from the WT and α1Q266I mutant mice with and without sustained perfusion of DH-CBD (20 μM) for 6 min (n=10-12). WT VS Q266I, p=0.045, unpaired t-test; Q266I VS Q266I+DH-CBD, p=0.55, unpaired t-test. (c) The average amplitude of Gly sIPSC in spinal slices obtained from the WT and α1Q266I mutant mice with and without sustained perfusion of DH-CBD (20 μM) for 6 min (n=10-12). WT VS Q266I, p=0.048, unpaired t-test; Q266I VS Q266I+DH-CBD, p=0.63, unpaired t-test.

Supplementary Figure 6 The effect of PTX on the Gly sIPSC amplitdue in spinal slices obtained from the α1R271Q mutant mice.

The average amplitude of Gly sIPSC in spinal slices obtained from the mutant mice with and without sustained perfusion of DH-CBD (20 μM) for 6 min. Each bar represents the average from 8 cells.

Supplementary Figure 7 DH-CBD restores seizure-like behavior in homozygous M287L mice.

(a) Time course curves of seizure occurrence in homozygous M287L mice and wild type littermates during developmental stage. The seizure-like bebavior occurred after P12-14 in M287L mutant mice. Each data point represents the average lasting time (s) of seizure occurrence per min from 6-7 mice (Day 8-12, p>0.6, unpaired t-test; Day 14-32, p<0.05, unpaired t-test). (b) Time course curves of seizure occurrence after intraperitoneal injection of DH-CBD (50 mg/kg) in M287L mutant mice (P16-18). Each data point represents the average lasting time (s) of seizure occurrence per min from 5-7 mice. Time=10 min, WT VS M287L homo (homozygous), p=0.016, unpaired t-test; M287L homo+vehicle VS M287L homo+DH-CBD, p=0.0073, unpaired t-test.

Supplementary Figure 8 Cannabinoid sensitive presynaptic GlyRs as a primary therapeutic target in the treatment of familial startle disease.

(a) Localization of tested hyperekplexia mutations in the α1 GlyR subunit. The mutations occurring in those GlyRs sensitive to cannabinoid are highlighted in blue, and the mutations occurring in those GlyRs insensitive to cannabinoid are highlighted in red. (b) Differential sensitivity of the mutant α1homomer and heteromer to cannabinoid-induced rescue of impaired GlyR Cl- channel activity. (c) Different states of presynaptic and postsynaptic mutant GlyRs in the presence or absence of cannabinoid in synapses containing hyperekplexic mutant α1 GlyRs.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 719 kb)

Supplementary Video 1

Exaggerated startle response to sound stimuli of the α1R271Q mutant mouse prior to DH-CBD administration. (MP4 4320 kb)

Supplementary Video 2

Exaggerated startle response to sound stimuli of the α1R271Q mutant mouse 5 min after administration of DH-CBD (30 mg/kg, i.p.). (MP4 1631 kb)

Supplementary Video 3

Delayed righting reflex of the α1R271Q mutant mouse prior to DH-CBD administration. (MP4 1798 kb)

Supplementary Video 4

Righting reflex of the α1R271Q mutant mouse 5 min after administration of DH-CBD (30 mg/kg, i.p.). (MP4 925 kb)

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Xiong, W., Chen, SR., He, L. et al. Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease. Nat Neurosci 17, 232–239 (2014). https://doi.org/10.1038/nn.3615

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