Synaptic density in the hippocampus of depressed patients: A quantitative electron microscopic study

Sebők-Tornai, Abigél and Csabai, Dávid and Szocsics, Péter and Gombás, Péter and Cobb, Justin A. and Mahajan, Gouri J. and Stockmeier, Craig A. and Czéh, Boldizsár (2026) Synaptic density in the hippocampus of depressed patients: A quantitative electron microscopic study. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 146. No. 111661. ISSN 0278-5846

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Abstract

Background: Synaptic dysfunction or loss of synapses is implicated in the pathophysiology of major depressive disorder (MDD). Recent in vivo functional neuroimaging studies document reduced number of synapses in the brains of MDD patients. Here, we performed a post-mortem quantitative electron microscopic study to confirm the putative synaptic loss in the hippocampus of patients with depression. Methods: Hippocampal tissue from subjects with MDD (n = 11, aged 19–79 years) and psychiatrically healthy controls (n = 17, aged 18–77 years) were investigated. A systematic quantitative analysis was performed to determine the synaptic densities based on unbiased counting principles. Neuropil of the three main subareas of the hippocampal formation (dentate gyrus, CA3, and CA1) were examined. Results: Hippocampal synaptic densities were comparable between control and depressed subjects. The average density of hippocampal synapses was 3.6 ± 0.2/μm3 in controls and 3.5 ± 0.2/μm3 in MDD patients. A more focused analysis however revealed that synaptic densities were significantly lower in the CA3 area of a subset of MDD patients with a single depressive episode. Age had no effect on synaptic density. Limitations: The sample size of the cohorts was relatively small. Only one segment of the rostral hippocampal body was analyzed. Conclusions: Our study provides further evidence that synaptic changes may contribute to the pathophysiology of MDD. We did not find the expected widespread synapse loss, instead a region-specific reduction was observed only in a subset of patients. The methodological limitations of our study may explain the contradiction between the results of in vivo neuroimaging data and the present post-mortem findings.

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