| Description |
The cellular processes that govern neuronal function are highly complex and tightly regulated in order to perform the elaborate information processing achieved by the brain. This is particularly evident in the trafficking of membrane proteins to and from synapses, which can travel long distances away from the cell body. Regulation of neurotransmitter receptors such as the AMPA-type glutamate receptor (AMPAR), the major excitatory neurotransmitter receptor in the brain, is a crucial mechanism for the modulation of synaptic transmission. Yet, the mechanisms by which AMPARs are transported over long distances are still unclear. We have addressed this question through genetic, cell biological and electrophysiological analysis of the C. elegans AMPAR GLR-1. This dissertation describes the role of long-range transport of AMPARs in the regulation of synaptic strength and provides insights into the cellular mechanisms underlying learning and memory. The pair of interneurons AVA expresses GLR-1 and are part of a welldefined circuit regulating the forward and backward movement of C. elegans in response to sensory inputs. To determine the mechanism for GLR-1 delivery to a synapse, we monitored the real-time trafficking of a fluorescently tagged GLR-1 chimera in AVA. We show that UNC-116, the C. elegans homolog of the vertebrate kinesin-1 (KIF5), is responsible for mediating the rapid, bidirectional transport of GLR-1. This motor-driven transport of GLR-1 modifies synaptic strength by mediating the rapid delivery, removal and redistribution of synaptic AMPARs. In the absence of unc-116, we found that although homomeric GLR-1 AMPARs can still diffuse to and accumulate at proximal synapses, glutamategated currents are decreased due to lack of heteromeric GLR-1/GLR-2-containing AMPARs. Furthermore, we show that transient expression of UNC- 116 can rescue defective glutamatergic signaling in adult unc-116 mutants, demonstrating that motor-dependent transport is ongoing in the adult nervous system and is involved in the regulation of synaptic strength. These data have allowed us to establish a link between motor-dependent transport of AMPARs and the strength of synaptic transmission. |
