DYT1 or DYT-TOR1A
dystonia is early-onset, generalized
dystonia. Most
DYT1 dystonia patients have a heterozygous trinucleotide GAG deletion in
DYT1 or TOR1A gene, with a loss of a
glutamic acid residue of the
protein torsinA.
DYT1 dystonia patients show reduced striatal
dopamine D2 receptor (D2R) binding activity. We previously reported reduced striatal D2R
proteins and impaired corticostriatal plasticity in
Dyt1 ΔGAG heterozygous knock-in (
Dyt1 KI) mice. It remains unclear how the D2R reduction contributes to the pathogenesis of
DYT1 dystonia. Recent knockout studies indicate that D2R on
cholinergic interneurons (Chls) has a significant role in corticostriatal plasticity, while D2R on medium spiny neurons (MSNs) plays a minor role. To determine how reduced D2Rs on ChIs and MSNs affect motor performance, we generated ChI- or MSN-specific D2R conditional knockout mice (Drd2 ChKO or Drd2 sKO). The striatal ChIs in the Drd2 ChKO mice showed an increased firing frequency and impaired
quinpirole-induced inhibition, suggesting a reduced D2R function on the ChIs. Drd2 ChKO mice had an age-dependent deficient performance on the beam-walking test similar to the
Dyt1 KI mice. The Drd2 sKO mice, conversely, had a deficit on the rotarod but not the beam-walking test. Our findings suggest that D2Rs on Chls and MSNs have critical roles in motor control and balance. The similarity of the beam-walking deficit between the Drd2 ChKO and
Dyt1 KI mice supports our earlier notion that D2R reduction on striatal ChIs contributes to the pathophysiology and the motor symptoms of
DYT1 dystonia.