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Published on: July 18, 2019
Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in Mice Carrying the Human Pathogenic Mutation
Dayana Rodriguez-Contreras1, Sheng Gong1, Joseph J Lebowitz1
1Research Service, VA Portland Health Care System, Portland, Oregon (D.R.-C., T.J.P., K.A.N.); Department of Behavioral Neuroscience (D.R.-C., T.J.P., K.A.N.), Transgenic Mouse Models Shared Resource (L.M.F.), and Vollum Institute (J.J.L., J.T.W.), Oregon Health & Science University, Portland, Oregon; Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado (S.G., C.P.F.); Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio (S.G., C.P.F.); and New York University Abu Dhabi, Saadiyat Island, Abu Dhabi, United Arab Emirates (N.A., T.M.D.).
A novel dopamine D2 receptor mutation (D2-I212F) causes a hyperkinetic movement disorder. Mice engineered with this mutation exhibit gait abnormalities and altered dopamine receptor function, confirming its pathogenicity.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- A novel dopamine D2 receptor mutation, D2-I212F, was identified in a family with a hyperkinetic movement disorder.
- This variant is a constitutively active and G protein-biased receptor.
Purpose of the Study:
- To engineer mice carrying the D2-I212F variant using CRISPR-Cas9.
- To investigate the pathogenicity of the D2-I212F mutation and its effects on dopamine receptor function.
- To establish a mouse model for studying early-onset hyperkinetic movement disorders.
Main Methods:
- CRISPR-Cas9 gene editing to create D2-I212F mutant mice (Drd2 mice).
- Assessment of gait abnormalities.
- Measurement of striatal D2 receptor expression.
- Electrophysiological recordings of dopamine neurons and striatum.
- Analysis of dopamine potency in different brain regions.
- Evaluation of cocaine treatment effects on dopamine potency.
Main Results:
- Drd2 mice displayed gait abnormalities consistent with chorea and/or dystonia.
- Striatal D2 receptor expression was reduced by approximately 30% per Drd2 allele.
- Inhibitory postsynaptic conductances showed significantly slower kinetics in Drd2 mice.
- Dopamine exhibited similar potencies in the nucleus accumbens and dorsal striatum of Drd2 mice, unlike wild-type mice.
- Repeated cocaine treatment did not alter dopamine potency in Drd2 mice.
Conclusions:
- The D2-I212F mutation is pathogenic and causes a hyperkinetic movement disorder.
- The engineered Drd2 mouse model accurately recapitulates key aspects of the human phenotype.
- This mouse model is valuable for further research into pathogenic DRD2 variants and for evaluating potential therapeutics.
