Enhanced Distal Signaling in Human Hippocampal Neurons despite Lower Intrinsic Excitability

The hippocampus is critical for memory and spatial navigation, and is central to the pathophysiology of temporal lobe epilepsy — the most common drug-resistant epilepsy. Yet our understanding of the cortico-hippocampal circuit, and neuronal function relies on rodent studies, which may not fully model human features. Here, we combined patch-clamp electrophysiology, histology, and microscopy to functionally and morphologically characterize human hippocampal neuron types at high-resolution from freshly resected tissue from epilepsy patients. We found striking region-, species, and pathology-specific differences in neuronal excitability, synaptic dynamics, and dendritic branch patterns. Dentate gyrus granule cells are the most excitable human hippocampal principal neurons. Human neurons are intrinsically less excitable than mouse neurons—requiring more current to fire—but paradoxically show higher action potential firing rates. Human pyramidal neurons from non-sclerotic CA1 show reduced sag compared to their sclerotic tissue, and its mouse counterpart. Human neurons more effectively preserve distal dendritic signal propagation to the soma. Neurons in each hippocampal sub-region display distinct activity-dependent synaptic plasticity dynamics. Morphologically, human neurons are larger with more elaborate and diverse dendritic branching patterns. Taken together, our results suggest that human hippocampal principal neurons have evolved in form and function to enhance synaptic input integration, and signaling.