Presenilin and APP regulate synaptic kainate receptors

bioRxiv (2022)

Barthet, G., Moreira-de-Sa, A., Zhang, P., Castanheira, J., Gorlewicz, A., Mulle, C

Kainate receptors (KARs) form a family of ionotropic glutamate receptors which regulate the activity of neuronal networks by both pre- and post-synaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (APP/PS1) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells with a genetic deletion of either presenilin or APP/APLP2 as well as in organotypic cultures treated with γ-secretase inhibitors. Finally, the GluK2 protein interacts with full-length and C-terminal fragments of APP. Overall, our data suggest that APP stabilizes KARs at synapses, possibly through a trans-synaptic mechanism, and this interaction is under the control the γ-secretase proteolytic activity of presenilin.