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    Modulation of neurogenesis and apoptosis in the adult enteric nervous system

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    Parisien, Catherine
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    Abstract
    Gastrointestinal (GI) disorders are often accompanied by a loss of enteric neurons, leading to GI dysfunction. Although a population of enteric neural stem cells (ENSCs) resides within the adult enteric nervous system (ENS), postnatal neurogenesis has been difficult to demonstrate in vivo. However, when enteric neurons are dissociated in culture, the brake on neurogenesis is released and ENSCs give rise to new neurons. Thus, the disruption of neuronal networks appears to release the proliferative brake on adult ENSCs. We hypothesized that neurotransmission is the factor that is disrupted by dissociation which may inhibit the proliferation of NSCs within the adult ENS, and that removal of this inhibition will give rise to neurogenesis. Longitudinal muscle and myenteric plexus (LMMP) preparations from adult mouse colon were organotypically cultured in vitro for one week while inhibiting various forms of neurotransmission. Immunohistochemistry for Human C/D (HuC/D) was used to identify myenteric neurons while the thymidine analogue, ethynyl deoxyuridine (EdU), was used as a marker of cell proliferation to detect neurogenesis. Inhibition of cholinergic, purinergic, serotonergic, and nitrergic neurotransmission increased enteric neurogenesis. Surprisingly, although neurogenesis increased, neuronal number remained constant. Inhibiting apoptosis in vitro using the pan-caspase inhibitor zVAD-fmk (80 µM) increased neuronal number within the myenteric plexus but had no effect on neurogenesis. Furthermore, inhibition of nitrergic neurotransmission using 7-nitroindazole (7-NI; 30 µM), in the presence of zVAD, led to an increase in neurogenesis and enteric neuronal number. However, when attempting to recreate our findings in vivo, inhibition of nitrergic neurotransmission, using 7-NI (30 mg/kg), had no effect on neurogenesis or neuronal density within the myenteric plexus. Together, our results indicate neurotransmission modulates the proliferative capacity of ENSCs, but caspase-dependent apoptosis regulates the neuronal population in vitro. By understanding the mechanisms underlying enteric neurogenesis, a viable therapeutic avenue to restore enteric innervation following GI injury may be identified.
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    http://hdl.handle.net/1974/26618
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