AbstractKainate receptors (KARs) are glutamate-gated ion channels that regulate neuronal excitability and network function in the brain. They can signal through both canonical ionotropic and a non-canonical metabotropic pathway. They regulate neuronal excitability by undergoing plasticity themselves while also regulating plasticity of other receptors. Most KARs contain the subunit GluK2 and the precise properties of these GluK2-containing KARs are determined by additional factors including ADAR2-mediated mRNA editing of a single codon that changes a genomically encoded glutamine (Q) to an arginine (R), which affects their assembly, trafficking and channel properties.
I initially set out to study the role of KARs in various forms of plasticity including long term potentiation (LTP) and long term depression (LTD) of AMPA receptors (AMPAR) and homeostatic scaling of KARs themselves. I was unable to reliably replicate previous data showing transient KAR stimulation leads to their increased surface expression which in turn increases AMPAR surface expression. Interestingly however, I discovered that sustained KAR stimulation decreased AMPAR surface expression leading to AMPAR LTD.
In addition, I identified that KARs undergo homeostatic plasticity whereby they upscale and downscale in response to changes in the network activity. My findings show that ADAR2-dependent Q/R editing of GluK2 is dynamically regulated during homeostatic plasticity elicited by the suppression of synaptic activity. This suppression of synaptic activity decreases ADAR2 levels by enhancing their proteasomal degradation, which selectively reduces the numbers of GluK2 subunits that are edited. This loss of editing results in increased KAR oligomerisation and ER exit to increase the surface expression of GluK2-containing KARs. Furthermore, I show that partial ADAR2 knockdown phenocopies and occludes TTX-induced scaling of KARs. These data indicate that activity-dependent regulation of ADAR2 levels and GluK2 Q/R editing provides a mechanism for KAR homeostatic plasticity.
|Date of Award||23 Jan 2019|
|Supervisor||Jeremy M Henley (Supervisor)|