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Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11229-11234. doi: 10.1073/pnas.1711351114. Epub 2017 Oct 2.

Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome.

Author information

1
Department of Pharmacology, University of Washington, Seattle, WA 98195.
2
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195.
3
Department of Pharmacology, University of Washington, Seattle, WA 98195; wcatt@uw.edu.

Abstract

Worldwide medicinal use of cannabis is rapidly escalating, despite limited evidence of its efficacy from preclinical and clinical studies. Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel NaV1.1. The duration and severity of thermally induced seizures and the frequency of spontaneous seizures were substantially decreased. Treatment with lower doses of CBD also improved autistic-like social interaction deficits in DS mice. Phenotypic rescue was associated with restoration of the excitability of inhibitory interneurons in the hippocampal dentate gyrus, an important area for seizure propagation. Reduced excitability of dentate granule neurons in response to strong depolarizing stimuli was also observed. The beneficial effects of CBD on inhibitory neurotransmission were mimicked and occluded by an antagonist of GPR55, suggesting that therapeutic effects of CBD are mediated through this lipid-activated G protein-coupled receptor. Our results provide critical preclinical evidence supporting treatment of epilepsy and autistic-like behaviors linked to DS with CBD. We also introduce antagonism of GPR55 as a potential therapeutic approach by illustrating its beneficial effects in DS mice. Our study provides essential preclinical evidence needed to build a sound scientific basis for increased medicinal use of CBD.

KEYWORDS:

Dravet syndrome; Scn1a; autism; cannabidiol; epilepsy

PMID:
28973916
PMCID:
PMC5651774
DOI:
10.1073/pnas.1711351114
[Indexed for MEDLINE]
Free PMC Article

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