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 (G alpha(olf)), 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 G alpha(olf)-deficient mice (Gnar(+/-)) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnarl(-/-)) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnarl(+/-)) with a 13 base pair deletion in the first exon of the rat Goal splicing variant 2, a major isoform in both human and rat striatum. Gnarl(+/-) 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 Gnarl(+/-) 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 G alpha(olf) function and finding a suitable treatment for dystonia associated with deficient dopamine transmission.

Yu-Taeger, L., Ott, T., Bonsi, P., Tomczak, C., Wassouf, Z., Martella, G., et al. (2020). Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia. NEUROBIOLOGY OF DISEASE, 134, 104634 [10.1016/j.nbd.2019.104634].

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

Ott T.;Martella G.;Sciamanna G.;Ponterio G.;Tassone A.;Pisani A.
;
2020-02-01

Abstract

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 (G alpha(olf)), 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 G alpha(olf)-deficient mice (Gnar(+/-)) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnarl(-/-)) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnarl(+/-)) with a 13 base pair deletion in the first exon of the rat Goal splicing variant 2, a major isoform in both human and rat striatum. Gnarl(+/-) 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 Gnarl(+/-) 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 G alpha(olf) function and finding a suitable treatment for dystonia associated with deficient dopamine transmission.
feb-2020
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/26 - NEUROLOGIA
English
Con Impact Factor ISI
AMPA receptor; Adenosine signaling; Arc; Dopamine signaling; GNAL; Knockout; LTD; Locomotor activity; Rat model
Yu-Taeger, L., Ott, T., Bonsi, P., Tomczak, C., Wassouf, Z., Martella, G., et al. (2020). Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia. NEUROBIOLOGY OF DISEASE, 134, 104634 [10.1016/j.nbd.2019.104634].
Yu-Taeger, L; Ott, T; Bonsi, P; Tomczak, C; Wassouf, Z; Martella, G; Sciamanna, G; Imbriani, P; Ponterio, G; Tassone, A; Schulze-Hentrich, Jm; Goodchi...espandi
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/232989
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 18
social impact