RGD Reference Report - Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia.

Authors: Yu-Taeger, Libo  Ott, Thomas  Bonsi, Paola  Tomczak, Celina  Wassouf, Zinah  Martella, Giuseppina  Sciamanna, Giuseppe  Imbriani, Paola  Ponterio, Giulia  Tassone, Annalisa  Schulze-Hentrich, Julia M  Goodchild, Rose  Riess, Olaf  Pisani, Antonio  Grundmann-Hauser, Kathrin  Nguyen, Huu Phuc 
Citation: Yu-Taeger L, etal., Neurobiol Dis. 2020 Feb;134:104634. doi: 10.1016/j.nbd.2019.104634. Epub 2019 Oct 31.
RGD ID: 150429833
Pubmed: PMID:31678405   (View Abstract at PubMed)
DOI: DOI:10.1016/j.nbd.2019.104634   (Journal Full-text)

Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (Gαolf), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous Gαolf -deficient mice (Gnal+/-) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnal-/-) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnal+/-) with a 13 base pair deletion in the first exon of the rat Gnal splicing variant 2, a major isoform in both human and rat striatum. Gnal+/- rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnal+/- rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating Gαolf function and finding a suitable treatment for dystonia associated with deficient dopamine transmission.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dystonia  ISOGnal (Rattus norvegicus)150429833; 150429833 RGD 
dystonia  IMP 150429833 RGD 
dystonia  IMP 150429833; 150429833compared to wildtype controlsRGD 
dystonia  IMP 150429833compared to wildtype controls and heterozygotesRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cellular response to dopamine  IMP 150429833 RGD 
regulation of long-term synaptic depression  IMP 150429833 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal locomotor behavior  IMP 150429833 RGD 
abnormal locomotor behavior  IMP 150429833; 150429833compared to wildtype controlsRGD 
abnormal motor learning  IMP 150429833 RGD 
abnormal motor learning  IMP 150429833; 150429833compared to wildtype controlsRGD 
decreased synaptic depression  IMP 150429833 RGD 
decreased synaptic depression  IMP 150429833; 150429833compared to wildtype controlsRGD 
postnatal growth retardation  IMP 150429833 RGD 
postnatal growth retardation  IMP 150429833; 150429833compared to wildtype controls and heterozygotesRGD 
postnatal lethality  IMP 150429833 RGD 
postnatal lethality  IMP 150429833; 150429833compared to wildtype controls and heterozygotesRGD 
reduced long-term depression  IMP 150429833 RGD 
reduced long-term depression  IMP 150429833; 150429833compared to wildtype controlsRGD 
Objects Annotated

Genes (Rattus norvegicus)
Gnal  (G protein subunit alpha L)
Gnalem1Hpng  (G protein subunit alpha L; CRISPR/Cas9 induced mutant 1, Hpng)

Genes (Mus musculus)
Gnal  (guanine nucleotide binding protein, alpha stimulating, olfactory type)

Genes (Homo sapiens)
GNAL  (G protein subunit alpha L)


Additional Information