Hippocampal Pyramidal Neuron Size Differs Among Subfields: Implications for Subfield Parcellation

Abstract The hippocampus is integral for learning and memory and is targeted by multiple diseases and disorders such as anxiety, depression, epilepsy, and Alzheimer’s disease. Neuroimaging approaches frequently use hippocampal or subfield volumes as a standard measure of neurodegeneration, thus making it an essential biomarker to study. However, in vivo MRI lacks the resolution needed to accurately parcellate subfields, and histologic delineations rely on vague or outdated features. More so, several discrepancies exist in subfield segmentation among groups. The present study sought to advance the histology segmentation field by acquiring quantitative neuron width measurements of the hippocampal subfields from 18 postmortem human samples. Neuron widths were collected using Feret’s diameter on hippocampal pyramidal neurons at five distinct anterior-posterior levels. Measurements were collected from CA1, CA2, CA3, CA4 and subiculum and the uncinate (medial) counterparts (CA1u, CA2u, CA3u, Subu). Ten neurons were measured per subfield per level, resulting in a total of 5,430 measured neurons. Our measurements indicate the following order of neuron size: CA4 > CA3 = CA2 > CA1 = Sub > ParaSub > PreSub. We also observed that each medial (uncinate) subfield had smaller neurons than its lateral counterpart (e.g., CA1 > CA1u). Further, we found that right hemisphere hippocampi had significantly larger neurons than left hemisphere hippocampi, and that controls had larger neurons than early Braak & Braak staged cases. The findings provide quantitative ground truth histologic measures for pyramidal neurons within individual subfields and a reliable method to distinguish the subfields at differing anterior-posterior levels.