Kainate Receptor Editing and Plasticity of AMPARs

Abstract

Kainate receptors (KARs) are hetero-tetrameric glutamate-gated ion channels. KARs are assemblies of five core subunits (GluK1-GluK5) with the combination GluK2 and GluK5 likely being the most common. KARs can signal via both canonical ionotropic and non-canonical metabotropic pathways to regulate synaptic function, neuronal excitability and maintenance of network activity. Recent evidence has shown that transient activation of KARs can upregulate the surface expression of AMPARs to elicit LTP.

In this thesis I examined whether activation of KARs can induce long-term depression (LTD) of AMPARs. My results suggest that Kainate application increases phosphorylation of GluA1 at S845. Moreover, sustained activation of postsynaptic GluK2 subunit-containing KARs reduces surface AMPARs to induce a novel form of LTD of AMPARs (KAR-LTDAMPAR) that is mediated via an ionotropic pathway and is independent of NMDA or mGlu receptors. This KAR-evoked loss of surface AMPA receptors is occluded by inhibiting calcineurin. These data, together with the previously reported KAR-LTPAMPAR, demonstrate that KARs bidirectionally regulate synaptic AMPARs and synaptic plasticity.

Finally, I investigated how the trafficking and functions of KARs are regulated by Q/R RNA editing of the GluK2 subunit, by the enzyme adenosine de-aminase 2 (ADAR2). I show that GluK2 editing-deficient mice exhibit higher paired-pulse and frequency facilitation (PPF-FF) along with enhanced KAR/AMPAR ratio. Moreover, the KAR currents in these mice have faster 10-90% rise time and decay kinetics (𝛕decay) compared to their edited counterparts. Perhaps most interestingly, the GluK2 editing-deficient mice show impaired metabotropic KAR function supported by reduced inhibition of IsAHP. These results demonstrate that GluK2 Q/R editing is crucial in both the biophysical properties and signalling KARs.

Date of Award	2 Dec 2021
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jeremy M Henley (Supervisor) & Jack R Mellor (Supervisor)