Assessing the action of GluK1 overexpression on synaptic strength and plasticity in a mouse model of Down syndrome

Abstract

Kainate receptors belong to one subfamily of the glutamatergic receptors. This receptor family is composed by homo- or heterodimers of five different types of subunits named GluK1 to GluK5. The human gene coding for the kainate receptor subunit GluK1 (GRIK1) is located on the human chromosome 21 that triplicates in Down syndrome. In animal models of this disease, Grik1 is situated on the short triplicated segment of chromosome 16, the orthologous of human chromosome 21. Previous work on trisomic models has found an imbalance between excitatory and inhibitory hippocampal synaptic activity. In this study, we used Ts2Cje mouse model to investigate a putative link between a GluK1 excess of function and altered synaptic properties in the hippocampus of trisomic mice. Trisomic animals were differentiated from their diploid littermates (DLM) by multiplex qPCR. RTqPCR analysis revealed that Grik1 mRNA levels are increased by more than 50% in different structures of the trisomic brain. Despite the lack of GluK1 specific antibody, we found in electrophysiological experiments that the extra gene-copy produces an increase of GluK1 functional protein at the membrane of trisomic neurons. Hippocampal patch clamp recordings from CA1 neurons revealed significant increase in basal and evoked inhibitory drive onto pyramidal cells and interneurons from trisomic mice. Ts2Cje animals also presented impaired synaptic plasticity in hippocampal CA1 pyramidal cells. We also observed that GluK1 selective drugs may rescue the over-inhibition phenotype observed in trisomic mice. Our data support the implication of GluK1-containing kainate receptors in the control of network activity in the area CA1 of the hippocampus which is altered in Down syndrome. Further molecular and pharmacological experiments will reveal more details about the effect of GluK1 overexpression on synaptic physiology and pathophysiology of this disease.