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Peer-reviewedCC BY 4.0Proceedings of the National Academy of Sciences of the United States of America

Lysine crotonylation acts as an epigenetic switch for glutamate neurotransmission and spatial memory

  • Utsav Mukherjee1,2,3
  • Budhaditya Basu1,2
  • Pratyush Suryavanshi2,4
  • Stacy E. Beyer1,2
  • Saaman Ghodsi1,2
  • Nathan Robillard1,2
  • Yann Vanrobaeys1,2,5
  • Eric B. Taylor6,7
  • Joseph Glykys2,4
  • Ted Abel1,2
  • Snehajyoti Chatterjee1,2
7 affiliations
  1. 1Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
  2. 2Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242
  3. 3Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242
  4. 4Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
  5. 5Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA 52242
  6. 6Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242
  7. 7Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
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Abstract

Histone posttranslational modifications, particularly lysine acetylation (Kac), are critical epigenetic regulators of transcriptional programs underlying long-term memory consolidation. Beyond Kac, several other non-acetyl acylations have been identified with the ability to regulate transcription; however, their role in memory consolidation remains unknown. Here, we identify histone lysine crotonylation (Kcr) as a molecular switch for long-term memory and glutamatergic neurotransmission. We find that spatial learning induces distinct spatiotemporal patterns of Kcr across hippocampal subregions. Through genetic manipulations, we show that reducing hippocampal Kcr levels impairs memory, while increasing Kcr levels by means of crotonate administration enhances long-term memory. Single-nuclei transcriptome and chromatin accessibility analyses reveal that crotonate facilitates activation of genes regulating glutamate signaling. Cell–cell communication analysis further suggests a strengthening of glutamatergic signaling within hippocampal excitatory neurons following crotonate administration. Real-time fluorescence imaging with genetically encoded sensors functionally validates our multiomics and computational findings—demonstrating the role of Kcr in regulating presynaptic glutamate release and neuronal activity. In summary, our findings elucidate a key mechanism underlying long-term memory consolidation and excitatory neurotransmission, linking epigenetic events to synaptic function and behavior.

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Cite

BibTeXRIS
BibTeX
@article{mukherjee2026lysine,
  title = {{Lysine crotonylation acts as an epigenetic switch for glutamate neurotransmission and spatial memory}},
  author = {Utsav Mukherjee and Budhaditya Basu and Pratyush Suryavanshi and Stacy E. Beyer and Saaman Ghodsi and Nathan Robillard and Yann Vanrobaeys and Eric B. Taylor and Joseph Glykys and Ted Abel and Snehajyoti Chatterjee},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = oct,
  doi = {10.1073/pnas.2608460123},
  url = {https://doi.org/10.1073/pnas.2608460123},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lysine crotonylation acts as an epigenetic switch for glutamate neurotransmission and spatial memory
AU  - Utsav Mukherjee
AU  - Budhaditya Basu
AU  - Pratyush Suryavanshi
AU  - Stacy E. Beyer
AU  - Saaman Ghodsi
AU  - Nathan Robillard
AU  - Yann Vanrobaeys
AU  - Eric B. Taylor
AU  - Joseph Glykys
AU  - Ted Abel
AU  - Snehajyoti Chatterjee
PY  - 2026
DA  - 2026/10/28
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2608460123
UR  - https://doi.org/10.1073/pnas.2608460123
AB  - Histone posttranslational modifications, particularly lysine acetylation (Kac), are critical epigenetic regulators of transcriptional programs underlying long-term memory consolidation. Beyond Kac, several other non-acetyl acylations have been identified with the ability to regulate transcription; however, their role in memory consolidation remains unknown. Here, we identify histone lysine crotonylation (Kcr) as a molecular switch for long-term memory and glutamatergic neurotransmission. We find that spatial learning induces distinct spatiotemporal patterns of Kcr across hippocampal subregions. Through genetic manipulations, we show that reducing hippocampal Kcr levels impairs memory, while increasing Kcr levels by means of crotonate administration enhances long-term memory. Single-nuclei transcriptome and chromatin accessibility analyses reveal that crotonate facilitates activation of genes regulating glutamate signaling. Cell–cell communication analysis further suggests a strengthening of glutamatergic signaling within hippocampal excitatory neurons following crotonate administration. Real-time fluorescence imaging with genetically encoded sensors functionally validates our multiomics and computational findings—demonstrating the role of Kcr in regulating presynaptic glutamate release and neuronal activity. In summary, our findings elucidate a key mechanism underlying long-term memory consolidation and excitatory neurotransmission, linking epigenetic events to synaptic function and behavior.
SN  - 0027-8424
SN  - 1091-6490
ER  -