Enhanced Distal Signaling in Human Hippocampal Neurons despite Lower Intrinsic Excitability

Enhanced Distal Signaling in Human Hippocampal Neurons despite Lower Intrinsic Excitability | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Enhanced Distal Signaling in Human Hippocampal Neurons despite Lower Intrinsic Excitability Tanvi Butola, Vincent Robert, Buyong Kim, Werner Doyle, Fabliha Hussain, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7820914/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Health sciences/Diseases/Neurological disorders/Epilepsy Biological sciences/Neuroscience/Synaptic transmission Biological sciences/Neuroscience/Learning and memory/Hippocampus Biological sciences/Neuroscience/Neuronal physiology/Intrinsic excitability Biological sciences/Neuroscience/Synaptic plasticity Full Text Additional Declarations Yes there is potential Competing Interest. Orrin Devinsky equity and/or compensation from the following companies: Tilray, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, Ajna Biosciences, Blackrock Neurotech, and California Cannabis Enterprises (CCE). He has received consulting fees or equity options from Emotiv, Koomba, UCB Pharma, Ultragenyx, Tennis Social AI, Stoke Therapeutics, Praxis Precision Therapeutics, Spine Care. He is the managing partner of the PhiFund Ventures. Supplementary Files SupplementalInformationTables.pdf Enhanced Distal Signaling in Human Hippocampal Neurons despite Lower Intrinsic Excitability Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7820914","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":541135956,"identity":"c55acd8f-2d45-4f7c-88a6-1783fc0005ec","order_by":0,"name":"Tanvi Butola","email":"","orcid":"https://orcid.org/0000-0003-4350-0569","institution":"NYU Grossman School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tanvi","middleName":"","lastName":"Butola","suffix":""},{"id":541135957,"identity":"42c0af1a-318d-4b52-8f8c-5ac6c6bc45f1","order_by":1,"name":"Vincent Robert","email":"","orcid":"","institution":"Department of Neuroscience, 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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. 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