Hippocampal NMDA receptors (NMDARs) and NMDAR-dependent synaptic plasticity are widely considered as crucial substrates of long-term spatial memory, although their precise role remains uncertain. Here we show that GluN1ΔDGCA1 mice, lacking NMDARs in all dentate gyrus and dorsal CA1 principal cells, acquired the spatial reference memory watermaze task as well as Controls, despite impairments on the spatial reference memory radial maze task. In a novel spatial discrimination watermaze paradigm, using two visually identical beacons, GluN1ΔDGCA1 mice were impaired at using spatial information to inhibit selecting the decoy beacon, despite knowing the platform’s actual spatial location. This failure could suffice to impair radial maze performance despite spatial memory itself being normal. Thus, these hippocampal NMDARs are not essential for encoding or storing long-term, associative spatial memories. Instead, we demonstrate an important role for the hippocampus in using spatial knowledge to select between alternative responses that arise from competing or overlapping memories.
Highlights d Assembly of native AMPARs occurs in discrete steps defined by ER-resident interactors d ABHD6 nurses GluA monomers; FRRS1l/CPT1c complexes drive multimer-formation of GluAs d FRRS1l is a potent regulator of synapse maturation and synaptic plasticity d FRRS1l knockout phenocopies the severe intellectual disability of human patients
We demonstrate the fundamental importance of glutamate receptor B (GluR-B) containing AMPA receptors in hippocampal function by analyzing mice with conditional GluR-B deficiency in postnatal forebrain principal neurons (GluR-B ⌬Fb ). These mice are as adults sufficiently robust to permit comparative cellular, physiological, and behavioral studies. GluR-B loss induced moderate long-term changes in the hippocampus of GluR-B ⌬Fb mice. Parvalbumin-expressing interneurons in the dentate gyrus and the pyramidal cells in CA3 were decreased in number, and neurogenesis in the subgranular zone was diminished. Excitatory synaptic CA3-to-CA1 transmission was reduced, although synaptic excitability, as quantified by the lowered threshold for population spike initiation, was increased compared with control mice. These changes did not alter CA3-to-CA1 long-term potentiation (LTP), which in magnitude was similar to LTP in control mice. The altered hippocampal circuitry, however, affected spatial learning in GluR-B ⌬Fb mice. The primary source for the observed changes is most likely the AMPA receptor-mediated Ca 2ϩ signaling that appears after GluR-B depletion, because we observed similar alterations in GluR-B QFb mice in which the expression of Ca 2ϩ -permeable AMPA receptors in principal neurons was induced by postnatal activation of a Q/R-site editing-deficient GluR-B allele.
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