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

Ilaria Bertocchi (1, 2, 3) , Ahmed Eltokhi (4, 5) , Andrey Rozov (4, 6, 7) , Vivan Nguyễn Chi (6) , Vidar Jensen (8) , Thorsten Bus (4) , Verena Pawlak (4) , Marta Serafino (4) , Hannah Sonntag (4) , Boyi Yang (4, 9) , Nail Burnashev (10, 4) , Shi-Bin Li (4, 11) , Horst A Obenhaus (4, 12) , Martin Both (13) , Burkhard Niewoehner (14) , Frank N Single (4, 15) , Michael Briese (14, 16) , Thomas Boerner (14) , Peter Gass (17) , John Nick P Rawlins (14) , Georg Köhr (4, 17) , David M Bannerman (14) , Rolf Sprengel (4)

1 Max Planck Institute for Molecular Biomedicine
2 Department of Neuroscience Rita Levi Montalcini
3 Neuroscience Institute Cavalieri-Ottolenghi
4 Max-Planck-Institut
5 Hertie Institute for Clinical Brain Research [Tubingen]
6 Institute for Pathology Heidelberg
7 KFU - Kazan Federal University
8 UiO - University of Oslo
9 Tongji Medical College [HUST]
10 INMED - INSERM U1249 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
11 Stanford University
12 Kavli Institute for Systems Neuroscience
13 Universität Heidelberg
14 Department of Experimental Psychology, University of Oxford, Oxford, UK
15 Miltenyi Biotec
16 Univ. of Wuerzburg
17 Central Institute of Mental Health [Mannheim]

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

Mots clés: Channelopathies; Translational research

Domaines: Neurosciences [q-bio.NC]

Ilaria Bertocchi, Ahmed Eltokhi, Andrey Rozov, Vivan Nguyễn Chi, Vidar Jensen, et al.. Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice. Communications Biology, 2021, 4, ⟨10.1038/s42003-020-01538-4⟩. ⟨hal-03190522⟩