Septin5 deficiency impairs both recent and remote contextual fear memory

Septin-3 and Septin-5 are components of the septin cytoskeleton highly expressed in the nervous system, yet the extent of their shared and distinct roles is not fully understood. We recently demonstrated that Septin-3 regulates late-phase long-term potentiation (L-LTP)-dependent invasion of smooth endoplasmic reticulum (sER) into dentate gyrus (DG) spines. Septin3^−/− mice exhibit normal synaptic ultrastructure in the hippocampal DG, CA3, and CA1, yet the fraction of sER-containing spines is reduced; behaviorally, they show selective deficits in 1-day object recognition and 1-day contextual fear memory, whereas cued fear conditioning and contextual memory tested at 1 month are intact. Here, using adult male Septin5^−/− mice, we tested whether morphological and behavioral phenotypes identified in Septin3^−/− mice are shared or subunit-specific. Electron microscopy showed no detectable differences in synapse density, spine volume, and postsynaptic density (PSD) area in the hippocampal DG, CA3, and CA1, with an unchanged fraction of sER-containing spines relative to wild-type littermates. Behaviorally, Septin5^−/− mice were impaired in recent (1 day) and remote (1 month) contextual fear memory, but were normal in 1-day novel object recognition memory and in recent and remote cued fear memory. The shared and distinct structural and behavioral phenotypes observed in Septin5^−/− and Septin3^−/− mice suggest either sER-independent common mechanisms or subunit-specific ones for recent contextual fear memory deficit, and indicate a Septin-5-dependent contribution to remote contextual fear memory.