Calbindin-containing CA1 pyramidal cells support cognitive flexibility in spatial task in mice

The hippocampus, and particularly the dorsal CA1, is essential for spatial memory consolidation through sharp-wave ripple events (SWRs) that enable the transfer of information to cortical areas. Within the dorsal CA1, distinct pyramidal cell sub-populations of the deep and superficial layer may play distinct roles in the processing and updating of spatial information. Using a Cre-dependent mouseline, we were able to precisely target the superficial, Calbindin (CALB1+) PCs of the CA1. This allowed us to gain a deeper understanding of the connectivity of CALB1+ CA1 PCs to their SWR-propagating excitatory output partners within the Subiculum (SUB), the burst-firing SUB PCs and their functional relevance in spatial memory consolidation and recall. Retrograde rabies tracing revealed heterogeneous innervation of the VGlut2+ bursting PCs by both CA1 PC sub-layers, and showed that the majority of presynaptic inputs are located in the superficial CA1 PC layer. We were able to observe that this anatomically confirmed connection between CALB1+ CA1 PCs and both SUB PC subtypes is able to induce spiking more reliably in burst- than regular-firing SUB PCs. CNO-induced inhibition in a Barnes Maze task revealed that the experimental group showed reduced cognitive flexibility and were slower to adapt to re-location of the goal when CALB1+ CA1 PCs were inhibited during the recall (test), while both groups behaved similarly when consolidation was manipulated (training). Inhibition did not impact overall learning, strategy development or locomotor control. This suggests that CALB1+ CA1 PCs preferentially connect to bursting SUB PCs, and support cognitive flexibility needed to adapt to a changing environment, adding further proof to the functional relevance of laminar segregation of the CA1 and the hippocampus in spatial memory processes.