A pathogenic missense mutation in kainate receptors elevates dendritic excitability and synaptic integration through dysregulation of SK channels

Abstract

Numerous rare de novo variants that cause neurodevelopmental disorders (NDDs) occur within genes encoding synaptic proteins, including ionotropic glutamate receptors (iGluRs). However, in many cases it remains unclear how damaging missense variants affect brain function. Here we determined the physiological consequences of an NDD causing missense mutation in the GRIK2 kainate receptor (KAR) gene, that results in a single amino acid change p.Ala657Thr in the GluK2 receptor subunit. We engineered the equivalent mutation in the mouse Grik2 gene, yielding a GluK2(A657T) mouse, to better understand the human disorder and determine how hippocampal neuronal function is disrupted. Synaptic KAR currents in hippocampal CA3 pyramidal neurons from heterozygous A657T mice exhibited slow decay kinetics, consistent with incorporation of the mutant subunit into functional receptors. Unexpectedly, CA3 neurons demonstrated elevated action potential spiking due to down-regulation of the small conductance Ca2+ activated K+ channel (SK), which mediates the post-spike afterhyperpolarization (AHP). The reduction in SK activity resulted in increased CA3 dendritic excitability, increased EPSP-spike coupling and lowered the threshold for the induction of LTP of the associational commissural (AC) synapses in the distal dendrites of CA3 neurons. Pharmacological inhibition of SK channels in wild-type (WT) mice increased dendritic excitability and EPSP-spike coupling, mimicking the phenotype in A657T mice and suggesting a causative role for attenuated SK activity in aberrant excitability observed in the mutant mice. These findings demonstrate that a disease-associated missense mutation in GRIK2 leads to altered signaling through neuronal KARs, pleiotropic effects on neuronal and dendritic excitability, and implicate these processes in neuropathology in patients with genetic NDDs.