Dysregulated adult hippocampal neurogenesis in major depressive disorders

23/08/2026

AI Summary

Identified adult human hippocampal subgranular zone neurogenic lineage and a stalled neurogenic process in MDD linked to transcriptional regulation, stress reprogramming and interferon signalling.
Excitatory and inhibitory neurons show transcription factor network dysregulation causing excitatory-inhibitory imbalance, impaired synaptic plasticity and reduced metabolic capacity.
Genetic and epigenetic regulation with immune activation overlaps autoimmune, neurodevelopmental and neurodegenerative mechanisms, suggesting targets for therapies to restore hippocampal-dependent cognition.

AI Summary

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity.

Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression.

We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages.

Basic summary

Nat Med. 2026 Aug 21. doi: 10.1038/s41591-026-04571-8. Online ahead of print.

ABSTRACT

Major depressive disorder (MDD) is associated with reduced hippocampal volume, altered connectivity and negative memory bias, suggesting disrupted hippocampal plasticity. Dysregulated adult hippocampal neurogenesis is a potential contributor, but its relevance in humans and role in MDD remain unclear. Here we investigated the molecular basis of hippocampal dysfunction in nonmedicated individuals with MDD by integrating analyses of neurogenic trajectories, cell-type- and subfield-specific gene expression, chromatin accessibility and protein expression. We identify a neurogenic lineage in the adult human hippocampal subgranular zone and provide evidence for a stalled neurogenic process in MDD, associated with transcriptional regulation, stress-related reprogramming and interferon signaling across developmental stages. Excitatory and inhibitory neurons show dysregulation of transcription factor networks affecting cell states. Cellular stress, excitatory-inhibitory imbalance, impaired synaptic plasticity, reduced metabolic capacity and immune activation, underlie impaired neurogenesis and reduced hippocampus circuit plasticity. Findings indicate genetic and epigenetic regulation of gene expression in MDD, and overlapping pathogenetic mechanisms with autoimmune, neurodevelopmental and neurodegenerative diseases. This work provides a new understanding of the pathogenesis of hippocampus-dependent cognitive symptoms in MDD and suggests potential therapeutic targets.

PMID:42629468 | DOI:10.1038/s41591-026-04571-8

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