Ultrastructural Analysis of Nigrostriatal Dopaminergic Terminals in a
Knockin Mouse Model of DYT1 Dystonia
Abstract
DYT1 dystonia is a form of generalized dystonia associated with
abnormalities in striatal dopamine release in mouse models and likely in
humans. In the present study, we examined the possibility that
ultrastructural changes in the morphology of nigrostriatal dopamine
terminals could contribute to this neurochemical imbalance using a
Serial-Block Face/Scanning Electron Microscope (SBF/SEM) and
three-dimensional reconstruction approach to analyze striatal tyrosine
hydroxylase-immunoreactive (TH-IR) terminals and their synapses in a
DYT1(ΔE) Knockin (DYT1-KI) mouse model of DYT1 dystonia. Furthermore, to
study possible changes in vesicle packaging capacity of dopamine, we
used transmission electron microscopy to assess possible changes in the
size of synaptic vesicles in striatal dopamine terminals between wild
type (WT) and the DYT1-KI mice. Quantitative analysis of 80 fully
reconstructed TH-IR terminals in the WT and DYT1-KI mice indicate: 1) No
significant difference in the volume of TH-IR terminals between WT and
DYT1-KI mice, 2) No major change in the proportion of axo-spinous vs
axo-dendritic synapses formed by TH-IR terminals between the two groups,
3) No significant change in the post-synaptic density (PSD) area of
axo-dendritic synapses, while the PSDs of axo-spinous synapses were
significantly smaller in DYT1-KI mice, 4) No significant difference in
the mean volume of mitochondria between WT mice and 5) No significant
difference in the surface area of synaptic vesicles between the two
groups. Altogether, these findings suggest that abnormal morphometric
changes of nigrostriatal dopamine terminals and their post-synaptic
targets are unlikely to be a major source of reduced striatal dopamine
release in DYT1 dystonia.