Regulation and dysregulation of neuronal circuits by KARs.

Abstract Kainate receptors (KARs) constitute a family of ionotropic glutamate receptors (iGluRs) with distinct physiological roles in synapses and neuronal circuits. Despite structural and biophysical commonalities with the other iGluRs, AMPA receptors and NMDA receptors, their role as post-synaptic receptors involved in shaping EPSCs to transmit signals across synapses is limited to a small number of synapses. On the other hand KARs regulate presynaptic release mechanisms and control ion channels and signaling pathways through non-canonical metabotropic actions. We review how these different KAR-dependent mechanisms concur to regulate the activity and plasticity of neuronal circuits in physiological conditions of activation of KARs by endogenous glutamate (as opposed to pharmacological activation by exogenous agonists). KARs have been implicated in neurological disorders, based on genetic association and on physiopathological studies. A well described example relates to temporal lobe epilepsy for which the aberrant recruitment of KARs at recurrent mossy fiber synapses takes part in epileptogenic neuronal activity. In conclusion, KARs certainly represent an underestimated actor in the regulation of neuronal circuits, and a potential therapeutic target awaiting more selective and efficient genetic tools and/or ligands.