Functional analysis of dopaminergic systems in a DYT1 knock-in mouse model of dystonia

Abstract

The dystonias are a group of disorders characterized by involuntary twisting movements and abnormal posturing. The most common of the inherited dystonias is DYT1 dystonia, which is due to deletion of a single GAG codon (ΔE) in the TOR1A gene that encodes torsinA. Since some forms of dystonia have been linked with dysfunction of brain dopamine pathways, the integrity of these pathways was explored in a knock-in mouse model of DYT1 dystonia. In DYT1(ΔE) knock-in mice, neurochemical measures revealed only small changes in the content of dopamine or its metabolites in tissue homogenates from caudoputamen or midbrain, but microdialysis studies revealed robust decreases in baseline and amphetamine-stimulated extracellular dopamine in the caudoputamen. Quantitative stereological methods revealed no evidence for striatal or midbrain atrophy, but substantia nigra neurons immunopositive for tyrosine hydroxylase were slightly reduced in numbers and enlarged in size. Behavioral studies revealed subtle abnormalities in gross motor activity and motor coordination without overt dystonia. Neuropharmacological challenges of dopamine systems revealed normal behavioral responses to amphetamine and a minor increase in sensitivity to haloperidol. These results demonstrate that this DYT1(ΔE) knock-in mouse model of dystonia harbors neurochemical and structural changes of the dopamine pathways, as well as motor abnormalities.

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

“…For example, increased slips on the raised beam task have been described in Tor1a +/− simple KO mice and hMT1 transgenic mice that overexpress mutant ΔE human torsinA (Dang et al, 2005, Song et al, 2012, Zhao et al, 2008). Similar to our Ciz1 −/− mice, Thap1 C54Y/+ mice and hMT1 transgenic mice show reduced fall latencies on the accelerating rotarod (Ruiz et al, 2015, Song et al, 2012). Directions of change are not consistent across all murine models of dystonia, however.…”

Immunochemical localization of vesicular monoamine transporter 2 (VMAT2) in mouse brain

“…Disrupted monoaminergic transmission characterizes a variety of neurodegenerative and neuropsychiatric disorders, such as dystonia, Huntington’s disease, depression, attention deficit hyperactivity disorder, schizophrenia, and addiction (Creese et al, 1996; Eisenberg et al, 1988; Freis, 1954; Hornykiewicz, 1998; Klawans et al, 1972; Ritz et al, 1988; Song et al, 2012). In the case of Parkinson’s Disease (PD), presynaptic monoamine vesicle function is substantially disrupted, and this dysfunction is hypothesized to contribute to neuronal vulnerability in PD pathogenesis (Pifl et al, 2014).…”

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

“…SLC18A2 | fast-scan cyclic voltammetry | serotonin | norepinephrine F aulty monoamine neurotransmission is characteristic of many disorders, including Parkinson disease, depression, dystonia, attention deficit hyperactivity disorder, schizophrenia, addiction, and Huntington disease (1)(2)(3)(4)(5)(6)(7). Several strategies have been used to enhance monoamine signaling: administration of precursors to increase synthesis, inhibition of enzymes to prevent metabolism/degradation, inhibition of plasma membrane transporters to increase synaptic lifespan, and administration of receptor agonists to directly activate postsynaptic targets.…”