Pharmacological perturbation reveals deficits in D2 receptor responses in Thap1 null mice

Abstract

The primary dystonia DYT6 is caused by mutations in the transcription factor Thanatos-associated protein 1 (THAP1). To understand THAP1's functions, we generated mice lacking THAP1 in the nervous system. THAP1 loss causes locomotor deficits associated with transcriptional changes. Since many of the genes misregulated involve dopaminergic signaling, we pharmacologically challenged the two striatal canonical dopamine pathways: the direct, regulated by the D1 receptor, and the indirect, regulated by the D2 receptor. We discovered that depleting THAP1 specifically interferes with the D2 receptor responses, pointing to a selective misregulation of the indirect pathway in DYT6 with implications for pathogenesis and treatment.

Transgenic Mice for the Translational Study of Neuropathic Pain and Dystonia

“…These findings highlight the possible role of torsinB in dystonia pathogenesis [ 75 ]. DYT6 dystonia is due to mutations in the transcription factor Thanatos-associated protein 1 (thap1), which is a ubiquitously expressed transcription factor with DNA-binding and protein-interaction domains; furthermore, thap1-null conditional KO mice present with dysfunctions in the dopaminergic indirect pathway [ 76 ]. Incidentally, a heterozygote thap1 c54y or Δexon2 allele in the striatum and cerebellum confers alterations similar to those typical of DYT1 dystonia, including [ 77 ] eIF2α signaling, glutamate-induced LTD, synaptic plasticity and neuritogenesis.…”