Canna~Fangled Abstracts

Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

By April 5, 2013No Comments
 2014 Jan 5. doi: 10.1038/nn.3615. [Epub ahead of print]

pm8Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease.

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.
PMID:

 24390226
[PubMed – as supplied by publisher] nature neuroscience

At a glance

Figures index

FromPresynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

Nature Neuroscience

 17,
232–239

doi:10.1038/nn.3615

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Figures

  1. The [alpha]1R271Q mutation impairs GlyR function and causes exaggerated startle behavior in mice.

    Figure 1

    The α1R271Q mutation impairs GlyR function and causes exaggerated startle behavior in mice.

  2. DH-CBD rescues [alpha]1 R271Q mutation-induced GlyR deficiency and hyper-reflexia in mice.

    Figure 2

    DH-CBD rescues α1 R271Q mutation–induced GlyR deficiency and hyper-reflexia in mice.

  3. Site-specific restoration of hyperekplexic GlyR dysfunction and startle responses by DH-CBD.

    Figure 3

    Site-specific restoration of hyperekplexic GlyR dysfunction and startle responses by DH-CBD.

  4. Differential sensitivity of homomeric and heteromeric GlyRs to hyperekplexic mutations and DH-CBD.

    Figure 4

    Differential sensitivity of homomeric and heteromeric GlyRs to hyperekplexic mutations and DH-CBD.

  5. Rescue by DH-CBD of diminished glycine release in spinal slices from [alpha]1 R271Q mutant mice.

    Figure 5

    Rescue by DH-CBD of diminished glycine release in spinal slices from α1 R271Q mutant mice.

  6. Differential sensitivity of presynaptic and postsynaptic GlyRs to hyperekplexic mutation and rescue by DH-CBD.

    Figure 6

    Differential sensitivity of presynaptic and postsynaptic GlyRs to hyperekplexic mutation and rescue by DH-CBD.

Supplementary Figures

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

    Supplementary Figure 1

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

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

    Supplementary Figure 2

    The efficacy of DH-CBD potentiation of R271Q mutant GlyRs.

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

    Supplementary Figure 3

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

  4. Addition of the [beta] subunit does not alter protein expression of R271Q and WT receptors at the cell surfaces

    Supplementary Figure 4

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

  5. DH-CBD does not restore diminished glycinergic transmission in spinal slices from the [alpha]1Q266I mutant mice.

    Supplementary Figure 5

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

  6. The effect of PTX on the Gly sIPSC amplitdue in spinal slices obtained from the [alpha]1R271Q mutant mice.

    Supplementary Figure 6

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

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

    Supplementary Figure 7

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

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

    Supplementary Figure 8

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

 

 Video 1: Supplementary Video 1

Exaggerated startle response to sound stimuli of the α1R271Q mutant mouse prior to DH-CBD administration.
Video 2: 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.).
Video 3: Supplementary Video 3

Delayed righting reflex of the α1R271Q mutant mouse prior to DH-CBD administration.
Video 4: Supplementary Video 4

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

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