Format

Send to

Choose Destination
Neurobiol Dis. 2019 Jan 25;125:92-106. doi: 10.1016/j.nbd.2019.01.014. [Epub ahead of print]

Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome.

Author information

1
Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain.
2
Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Ctra Utrera km. 1, 41013 Seville, Spain.
3
Integrative Pharmacology and Systems Neuroscience Research Group, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain; CIBER Pathophysiology of Obesity and Nutrition, Institute of Health Carlos III, 28029 Madrid, Spain.
4
Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain; Department of Psychobiology and Methodology of Health Sciences, Universitat Autònoma de Barcelona, Spain.
5
Integrative Pharmacology and Systems Neuroscience Research Group, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain.
6
INSERM U1215, Neurocentre Magendie, Physiopathology and Therapeutic Approaches of Stress-Related Diseases, 33077 Bordeaux, France.
7
Center of Animal Biotechnology and Gene Therapy (CBATEG), Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; CIBER Diabetes and Associated Metabolic Disorders (CIBERDEM), 08017 Madrid, Spain.
8
Cellular & Systems Neurobiology, Systems Biology Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain; CIBER Rare Disorders (CIBERER), Spain; Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain.
9
Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003 Barcelona, Spain. Electronic address: andres.ozaita@upf.edu.

Abstract

Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

KEYWORDS:

Cannabinoid receptor type-1; Cognitive deficits; Down syndrome; Endocannabinoid system; Hippocampus; Intellectual disability

PMID:
30685352
DOI:
10.1016/j.nbd.2019.01.014

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center