Abstract
Parkinson’s disease (PD) is associated with neuronal damage in the brain and gut. This work compares changes in the enteric nervous system (ENS) of commonly used mouse models of PD that exhibit central neuropathy and a gut phenotype. Enteric neuropathy was assessed in five mouse models: peripheral injection of MPTP; intracerebral injection of 6-OHDA; oral rotenone; and mice transgenic for A53T variant human α-synuclein with and without rotenone. Changes in the ENS of the colon were quantified using pan-neuronal marker, Hu, and neuronal nitric oxide synthase (nNOS) and were correlated with GI function. MPTP had no effect on the number of Hu+ neurons but was associated with an increase in Hu+ nuclear translocation (P < 0.04). 6-OHDA lesioned mice had significantly fewer Hu+ neurons/ganglion (P < 0.02) and a reduced proportion of nNOS+ neurons in colon (P < 0.001). A53T mice had significantly fewer Hu+ neurons/area (P < 0.001) and exhibited larger soma size (P < 0.03). Treatment with rotenone reduced the number of Hu+ cells/mm2 in WT mice (P < 0.006) and increased the proportion of Hu+ translocated cells in both WT (P < 0.02) and A53T mice (P < 0.04). All PD models exhibited a degree of enteric neuropathy, the extent and type of damage to the ENS, however, was dependent on the model.
Highlights
Parkinson’s disease (PD) is associated with neuronal damage in the brain and gut
We investigated and directly compared mouse models of PD for enteric neuropathy and correlated these findings with GI dysfunction (assessed via bead expulsion, fecal pellet output (FPO) and fecal water content (FWC))
To determine whether the number of neurons per ganglion and ganglia per area was altered in different PD models, the number of Hu-IR neurons per ganglion and number of ganglia per area was assessed. 6-OHDA lesioned mice had significantly fewer Hu-IR neurons per ganglion than unlesioned controls (6-OHDA: 25.2 ± 2.3 neurons/ganglion, Sham: 34.9 ± 2.5 neurons/ganglion, P < 0.02, Fig. 2A,A’, Table 2), 6-OHDA mice had a higher density of ganglia per area when compared to unlesioned controls (6-OHDA: 18.2 ± 2.2 ganglia/are, Sham: 10.4 ± 0.6 ganglia/area, P < 0.01, Fig. 2C, Table 2)
Summary
This work compares changes in the enteric nervous system (ENS) of commonly used mouse models of PD that exhibit central neuropathy and a gut phenotype. GI dysfunction is highly prevalent, affecting 80–90% of PD patients, and includes symptoms such as dysphagia (difficulty swallowing), gastroparesis (slowed gastric emptying) and chronic constipation. These GI symptoms often precede the onset of motor deficits by decades[5]. Neuronal loss and neurochemical changes have been observed in the ENS of patients with PD, and a positive correlation between gut permeability and intestinal levels of aggregated α-syn has been observed in humans[9,10]. Conflicting results exist regarding whole gut transit time and stool frequency in the α-syn transgenic mouse model (which expresses the human A53T mutation), with delayed whole gut transit time and reduced fecal pellet output reported as early at 3 months of age in some studies[11,12], whilst other studies have failed to detect differences as late as 15 months of a ge[13,14]
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