Neuromuscular Junction Defects in Mice with Mutation of dynein heavy chain 1

Disruptions in axonal transport have been implicated in a wide range of neurodegenerative diseases. Cramping 1 (Cra1/+) and Legs at odd angles (Loa/+) mice, with hypomorphic mutations in the dynein heavy chain 1 gene, which encodes the ATPase of the retrograde motor protein dynein, were originally reported to exhibit late onset motor neuron disease. Subsequent, conflicting reports suggested that sensory neuron disease without motor neuron loss underlies the phenotypes of Cra1/+ and Loa/+ mice. Here, we present behavioral and anatomical analyses of Cra1/+ mice. We demonstrate that Cra1/+ mice exhibit early onset, stable behavioral deficits, including abnormal hindlimb posturing and decreased grip strength. These deficits do not progress through 24 months of age. No significant loss of primary motor neurons or dorsal root ganglia sensory neurons was observed at ages where the mice exhibited clear symptomatology. Instead, there is a decrease in complexity of neuromuscular junctions. These results indicate that disruption of dynein function in Cra1/+ mice results in abnormal morphology of neuromuscular junctions. The time course of behavioral deficits, as well as the nature of the morphological defects in neuromuscular junctions, suggests that disruption of dynein function in Cra1/+ mice causes a developmental defect in synapse assembly or stabilization

Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study

Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.DTI scans were acquired for 19 children and adolescents with ASD (∼8-18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8-18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder

Synaptic and post-synaptic defects at the neuromuscular junctions in <i>Cra1/+</i> mice.

<p>A) α-bungarotoxin and GFP labeled NMJs. (Scale bar  = 20 µm). B) Motor neuron axons reveal a decrease in the proportion of NMJs with complete overlap between pre and post-synaptic zones and a compensatory increase in the proportion of NMJs with partial overlap in <i>Cra1/+</i> mice (*P<0.05). C) Labeling of nuclei by DAPI stain demonstrates a significant increase in central nuclei in <i>Cra1/+</i> mice, a measure of muscle fiber degeneration and regeneration (central nuclei indicated with red arrow; *P<0.05; N = 3 mice per genotype).</p

<i>Cra1</i>/+ mice show no evidence of proprioceptive sensory neuron loss at symptomatic ages.

<p>A) Proprioceptive sensory neuron labeling and quantification with parvalbumin, (B) ER81, and (C) TrkC shows no difference between of +/+ and <i>Cra1</i>/+ mice at 6 months of age (Scale bar  = 20 µm). D) Parvalbumin labeling of proprioceptive sensory neuron fibers within the spinal cord shows the central projection of these sensory neurons is intact in <i>Cra1</i>/+ mice (Scale bar  = 20 µm; N = 3 animals per genotype).</p