Distinct effects of AMPAR subunit depletion on spatial memory

Ahmed Eltokhi; Ilaria Bertocchi; Andrei Rozov; Vidar Jensen; Thilo Borchardt; Amy Taylor; Catia C Proenca; John Nick P Rawlins; David M Bannerman; Rolf Sprengel

doi:10.1016/j.isci.2023.108116

Distinct effects of AMPAR subunit depletion on spatial memory

iScience. 2023 Oct 1;26(11):108116. doi: 10.1016/j.isci.2023.108116. eCollection 2023 Nov 17.

Authors

Ahmed Eltokhi^{1

2}, Ilaria Bertocchi^{1

3

4}, Andrei Rozov^{1

5

6}, Vidar Jensen⁷, Thilo Borchardt¹, Amy Taylor⁸, Catia C Proenca¹, John Nick P Rawlins⁸, David M Bannerman⁸, Rolf Sprengel¹

Affiliations

¹ Departments of Molecular Neurobiology and Physiology, Max Planck Institute for Medical Research, Heidelberg, Germany.
² Department of Pharmacolog, University of Washington, Seattle, WA, USA.
³ Department of Neuroscience Rita Levi Montalcini, University of Turin, 10126 Turin, Italy.
⁴ Neuroscience Institute - Cavalieri-Ottolenghi Foundation (NICO), Laboratory of Neuropsychopharmacology, Regione Gonzole 10, Orbassano, 10043 Torino, Italy.
⁵ Institute of Neuroscience, Lobachevsky State University of Nizhniy, 603022 Novgorod, Russia.
⁶ Federal Center of Brain Research and Neurotechnology, 117997 Moscow, Russia.
⁷ Department of Molecular Medicine, Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway.
⁸ Department of Experimental Psychology, University of Oxford, Oxford, UK.

Abstract

Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3^-/-) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3^ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3^-/- mice showed premature mortality. Gria1/3^ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3^ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1^-/- and Gria3^-/- knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance.

Keywords: Cellular neuroscience; Molecular neuroscience.

Grants and funding

WT_/Wellcome Trust/United Kingdom