A Novel Transgenic Mouse Model to Investigate the Cell-Autonomous Effects of torsinA(ΔE) Expression in Striatal Output Neurons.

Dystonia is a disabling neurological syndrome characterized by abnormal movements and postures that result from intermittent or sustained involuntary muscle contractions; mutations of DYT1/TOR1A are the most common cause of childhood-onset, generalized, inherited dystonia. Patient and mouse model data strongly support dysregulation of the nigrostriatal dopamine neurotransmission circuit in the presence of the DYT1-causing mutation. To determine striatal medium spiny neuron (MSN) cell-autonomous and non-cell autonomous effects relevant to dopamine transmission, we created a transgenic mouse in which expression of mutant torsinA in forebrain is restricted to MSNs. We assayed electrically evoked and cocaine-enhanced dopamine release and locomotor activity, dopamine uptake, gene expression of dopamine-associated neuropeptides and receptors, and response to the muscarinic cholinergic antagonist, trihexyphenidyl. We found that over-expression of mutant torsinA in MSNs produces complex cell-autonomous and non-cell autonomous alterations in nigrostriatal dopaminergic and intrastriatal cholinergic function, similar to that found in pan-cellular DYT1 mouse models. These data introduce targets for future studies to identify which are causative and which are compensatory in DYT1 dystonia, and thereby aid in defining appropriate therapies.