Variation in the involvement of hippocampal pyramidal cell subtypes in spatial learning tasks

Hippocampal pyramidal cells are involved in spatial coding and memory formation. Recent evidence shows that they can be classified according to the origin of their axon, which either emerges from the soma (nonAcD for 'non-axon-carrying dendrite') or from a proximal basal dendrite (AcD). We have shown that AcD neurons account for ∼50% of CA1 pyramidal neurons and that they integrate excitatory inputs differently. They are less susceptible to perisomatic inhibition and are more strongly recruited during memory-related network oscillations with strong inhibitory activity. Here, we tested whether AcD and nonAcD neurons are differentially engaged during distinct stages of spatial learning. We trained mice of either sex on a spatial memory task (m-maze) and quantified cFos expression in CA1 pyramidal neurons at different training stages. AcD and nonAcD cells were distinguished by staining the axon initial segment. Across learning stages, dorsal and medio-ventral hippocampus showed distinct activation patterns. In dorsal CA1, cFos expression shifted from a predominant presence in nonAcD cells at early stages to increased presence in AcD cells at later stages. In medio-ventral CA1, AcD neurons showed a transient cFos expression peak at intermediate stages of the training, accompanied by a progressive reduction of the percentage of AcD cells over time. This reduction was not observable in the dorsal hippocampus. This suggests region- and cell type-dependent recruitment patterns of CA1 pyramidal cells during learning and indicates that the site of axon origin may undergo structural plasticity. In addition, the findings support a functional and structural differentiation along the dorso-ventral axis of CA1.Significance statement Neurons with axons emerging from dendrites (AcD cells) represent a morphologically and functionally discernible subpopulation of hippocampal pyramidal cells. Here, we show different involvement of AcD and nonAcD cells during different learning stages and hippocampal subregions. Remarkably, the proportion of AcD cells in the medio-ventral hippocampus dynamically decreases during learning, suggesting that the site of axon origin is structurally plastic. This discovery challenges the longstanding view of fixed neuronal wiring and identifies the axon-carrying dendrite as a site of adaptive structural reconfiguration. Our findings reveal a novel, plastic mechanism for tuning neuronal excitability during learning and highlight the dynamic interplay between morphology and function in hippocampal circuits.