Linking Anatomical and Physiological Properties of Hippocampal Pyramidal Neurons

Abstract

The hippocampus is of interest to a broad range of neuroscientists, who examine its structure, function, and dysfunction in various pathologies and disorders. Great effort has been put into classifying hippocampal neurons according to their morphological, molecular, and functional characteristics; however, the question of whether and how in vivo neural activity relates to principal cell heterogeneity during natural behaviour has remained unresolved. This study aimed at resolving structure-function relationships in the mouse dorsal hippocampus by investigating three dimensions of principal cell heterogeneity. First, we juxtacellularly recorded and labelled CA2/CA3 pyramidal neurons in freely-moving mice, thus linking quantitative features of dendritic architecture and anatomical position to in vivo activities. We found that a higher proportion of distal dendritic length correlated with higher burst propensity, indicating that entorhinal inputs may determine the burst-firing properties of CA2/CA3 pyramidal neurons. Second, we investigated CA1 principal cell diversity within the deep-superficial axis. We combined the juxtacellular recording technique with optogenetics in freely-moving animals. With restricted Channelrhodopsin (ChR2) expression in Calbindin-positive (Calb1+) neurons, we achieved online readout of cell identity via photostimulation, thus improving the sampling efficacy of superficial layer neurons. We found that Calb1+ CA1 pyramidal cells had weaker spatial modulation and contained less spatial information than Calbindin-negative (Calb1-) neurons, pointing to cell identity as a critical determinant for recruitment into the hippocampal spatial map. Lastly, we explored the anatomical determinants for the recruitment of pyramidal neurons by hippocampal sharp-wave ripple events. The axon initial segment location determined two distinct pyramidal cell types. Neurons with axons initiating from dendrites were more recruited into sharp-wave ripples, indicating that excitatory inputs onto axon-carrying dendrites can escape perisomatic inhibition during hippocampal ripples. Collectively, these results indicate that the recruitment of pyramidal neurons into hippocampal neural ensembles critically depends on cell identity and single cell morphological features.