Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice

• DOI: 10.1038/s42003-020-01538-4
• Publication Date: 2021-01-08T11:19:34Z
• Authors: Ilaria Bertocchi; Ahmed Eltokhi; Andrey Rozov; Vivan Nguyễn Chi; Vidar Jensen; Thorsten Bus; Verena Pawlak; Marta Serafino; Hannah Sonntag; Boyi Yang; Nail Burnashev; Shi-Bin Li; Horst A. Obenhaus; Martin Both; Burkhard Niewoehner; Frank N. Single; Michael Briese; Thomas Boerner; Peter Gass; John Nick P. Rawlins; Georg Köhr; David M. Bannerman; Rolf Sprengel
• Keywords: 0301 basic medicine; ddc:610; QH301-705.5; 610; Association Learning; Translational research; Hippocampus; Receptors, N-Methyl-D-Aspartate; Article; Epilepsy, Reflex; Mice; 03 medical and health sciences; Attention Deficit Disorder with Hyperactivity; Animals; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Channelopathies; Cognitive Dysfunction; [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Calcium Signaling; Biology (General); Proto-Oncogene Proteins c-fos; Spatial Memory

Abstract The NMDA receptor-mediated Ca 2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity thus has a key role the nervous system. In GRIN2 -variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures intellectual disability. By using our gene-targeted mouse line (Grin2a N615S ) , we show that voltage-independent glutamate-gated GluN2A-containing receptors associated with NMDAR-dependent audiogenic due hyperexcitable midbrain circuits. contrast, NMDAR antagonist MK-801-induced c-Fos expression hippocampus. Likewise, synchronization theta- gamma oscillatory lowered exploration, demonstrating hippocampal activity. This exploratory hyperactivity aberrantly increased dysregulated levels attention can interfere associative learning, particular when relevant cues reward outcomes are disconnected space time. Together, findings provide (i) experimental evidence inherent voltage-dependent essential for maintaining appropriate responses sensory stimuli (ii) mechanistic explanation neurological manifestations seen NMDAR-related human disorders variant-meidiated disability focal epilepsy.