A Novel Transgenic Mouse Model to Investigate the Cell-Autonomous Effects of torsinA(ΔE) Expression in Striatal Output Neurons. (1st December 2019)

• Record Type: Journal Article
• Authors: Gonzalez-Alegre, Pedro; Beauvais, Genevieve; Martin, Janine; Koch, Rick J.; Walker, Ruth H.; Patel, Jyoti C.; Rice, Margaret E.; Ehrlich, Michelle E.
• Is Part Of: Neuroscience. Volume 422(2019)
• Page Start: 1
• Page End: 11
• Publication Date: 2019-12-01
• Subjects: ChI cholinergic interneurons -- MSNs medium spiny neurons; Dystonia -- DYT1 -- Striatum -- Dopamine -- TH -- DARPP32; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.09.007
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Transgenic expression of torsinA(WT or ΔE) in striatal medium spiny neurons does not alter baseline mouse motor behavior. D9.torsinA(WT) transgenic mice have abnormal dopamine release from striatonigral axons. D9.torsinA(WT or ΔE) transgenic mice exhibit a normal response to cocaine. torsinA(ΔE) expression in nigral and striatal neurons weakens the influence of trihexyphenidyl on the response to cocaine. Abstract: 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.