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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-BΔFb). 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-BΔFb 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-BΔFb mice. The primary source for the observed changes is most likely the AMPA receptor-mediated Ca 2+ signaling that appears after GluR-B depletion, because we observed similar alterations in GluR-BΔFb mice in which the expression of Ca 2+-permeable AMPA receptors in principal neurons was induced by postnatal activation of a Q/R-site editing-deficient GluR-B allele. [ABSTRACT FROM AUTHOR]