| Abstract No.: | 207 |
| Country: | Canada |
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| Title: | INHIBITION INHIBITS NEUROGENESIS |
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| Authors/Affiliations: | 1 Pierre Drapeau*;
1 Universite de Montreal, Département de pathologie et biologie cellulaire, QC, Canada
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| Content: | Vertebrate embryos from fish to man have a depolarizing cellular chloride gradient that is postulated to be essential for development of the nervous system. Excitatory chloride-mediated signaling by glycine and GABA is often the first form of activity to emerge in the nascent vertebrate nervous system. We perturbed glycinergic transmission in vivo from the onset of development in zebrafish embryos and examined its impact on the formation of motor circuitry. Targeted knockdown of the embryonic glycine receptor alpha 2 subunit disrupted rhythm generating networks and reduced the frequency of spontaneous glycinergic and glutamatergic events. We observed a reduction in the number of spinal interneurons without changes in sensory and motor neuron populations. This effect was accompanied by a concomitant increase in the number of mitotic cells, suggesting that glycine signaling regulates interneuron differentiation during early development. Despite the loss of many interneurons a sub-threshold rhythm-generating circuit was still capable of forming. These data provide evidence that glycine receptors, in addition to their role in neurotransmission, regulate interneuron differentiation during development.
To explore the role of the underlying chloride gradient, we overexpressed the potassium-chloride co-transporter 2 (KCC2) in newly fertilized zebrafish embryos to reverse the chloride gradient in all neurons from the onset of development. This rendered glycine hyperpolarizing when tested at the time that motor behaviours (but not native KCC2) first appear. KCC2 overexpression resulted in fewer mature spontaneously active spinal neurons, more immature silent neurons, and disrupted motor activity. We observed fewer motoneurons and interneurons, a reduction in the size of axonal tracts and smaller brains and spinal cords. However, we observed no increased cell death and a normal complement of sensory neurons, glia and progenitors.
These results suggest that chloride-mediated excitation plays a crucial role in promoting neural differentiation from the earliest stages of embryonic development and that later chloride-mediated inhibition normally limits this process. We are currently examining whether there is a generalized neurogenic action or a more selective regulation of the development of subsets of interneurons during this earliest activity-dependent process.
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