Biology subjects

Downs, A. M.

Publications and source records attributed to Downs, A. M..

3 recordsLinked to original sources

bioRxiv2021

Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although basal ganglia dysfunction is implicated in many forms of dystonia, the underlying mechanisms are unclear. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented whereas proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated proteins identified in our screen are associated with pathogenic variants that cause inherited dystonic disorders in humans suggesting shared mechanisms across many different forms of dystonia.

neuroscience↗

bioRxiv2020

Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of DYT1-TOR1A dystonia

DYT1-TOR1A dystonia is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1A{Delta}E). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a({Delta}E) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a({Delta}E) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a({Delta}E) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a({Delta}E) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/{Delta}E knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a({Delta}E) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a({Delta}E) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a({Delta}E) mutation within dopamine neurons.

neuroscience↗

bioRxiv2020

BLOCKADE OF M4 MUSCARINIC RECEPTORS ON STRIATAL CHOLINERGIC INTERNEURONS NORMALIZES STRIATAL DOPAMINE RELEASE IN A MOUSE MODEL OF DYT1-TOR1A DYSTONIA

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is commonly used for the treatment of dystonia associated with TOR1A, otherwise known as DYT1 dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. We previously found that THP normalizes the deficit in striatal dopamine (DA) release in a mouse model of TOR1A dystonia (Tor1a+/{Delta}E knockin (KI) mice), revealing a plausible mechanism of action for this compound, considering that abnormal DA neurotransmission is consistently associated with many forms of dystonia. However, the mAChR subtype(s) that mediate the rescue of striatal dopamine release remain unclear. In this study we used a combination of pharmacological challenges and cell-type specific mAChR conditional knockout mice of either sex to determine which mAChR subtypes mediate the DA release-enhancing effects of THP. We determined that THP acts in part at M4 mAChR on striatal cholinergic interneurons to rescue DA release in both Tor1a+/+ and Tor1a+/{Delta}E KI mice. Further, we found that the subtype selective M4 antagonist VU6021625 recapitulates the effects of THP. These data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that subtype selective M4 mAChR antagonists may be effective therapeutics with fewer side effects than THP for the treatment of TOR1A dystonia.

pharmacology and toxicology↗