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Background <p>Synaptic plasticity, a fundamental process underlying learning and memory, depends on activity-driven changes in neural connectivity. S-palmitoylation, a reversible post<i>-</i>translational lipid modification, modulates synaptic protein function by influencing protein conformation, localization, trafficking, and molecular interactions. Despite its known significance in neuronal function, the temporal and protein-specific dynamics of S-palmitoylation during synaptic plasticity remain poorly understood.</p> Methodology &amp; Principal Findings <p>Using electrophysiological methods, molecular biology, proteomics, and imaging across various models (neuronal cultures, hippocampal slices, and synaptoneurosomes), we investigated S-palmitoylation during synaptic activity. Induction of long-term potentiation (LTP) resulted in protein-specific palmitoylation changes without altering global levels. In hippocampal slices, synaptophysin and PSD95 displayed distinct temporal patterns of palmitoylation, influenced by LTP. Deacylation experiments using N-(tert<i>-</i>butyl)hydroxylamine (NtBuHA) demonstrated that protein S-palmitoylation is crucial for organizing neuronal spiking and enabling LTP, particularly in the stratum radiatum. Mass spectrometry of synaptoneurosomes revealed a palmitoylome including over 700 proteins, with stimulation-induced predominant depalmitoylation. Differentially palmitoylated proteins were associated with synaptic vesicle cycling, cytoskeletal dynamics, and neurotransmitter release. What is interesting is that synaptoneurosomes contained active palmitoylation machinery, supporting rapid, target<i>-</i>specific responses to NMDA receptor activation.</p> Conclusions <p>Temporal and protein-specific S-palmitoylation emerges as a vital mechanism for synaptic plasticity, contributing to neuronal network function and memory formation. These findings elucidate how palmitoylation acts as a dynamic regulator of synaptic activity and offer insights into its regulation. The study highlights the potential of targeting palmitoylation pathways for enhancing neuronal function.</p>

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Temporal and protein-specific S-palmitoylation supports synaptic and neural network plasticity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月11日

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  • Agata Pytyś,
  • Rabia Ijaz,
  • Anna Buszka,
  • Jacek Miłek,
  • Izabela Figiel,
  • Patrycja Wardaszka-Pianka,
  • Matylda Roszkowska,
  • Natalia Mierzwa,
  • Adam Wojtas,
  • Eli Kerstein,
  • Remigiusz Serwa,
  • Katarzyna Kalita,
  • Rhonda Dzakpasu,
  • Magdalena Dziembowska,
  • Jakub Włodarczyk,
  • Tomasz Wójtowicz

摘要

Background

Synaptic plasticity, a fundamental process underlying learning and memory, depends on activity-driven changes in neural connectivity. S-palmitoylation, a reversible post-translational lipid modification, modulates synaptic protein function by influencing protein conformation, localization, trafficking, and molecular interactions. Despite its known significance in neuronal function, the temporal and protein-specific dynamics of S-palmitoylation during synaptic plasticity remain poorly understood.

Methodology & Principal Findings

Using electrophysiological methods, molecular biology, proteomics, and imaging across various models (neuronal cultures, hippocampal slices, and synaptoneurosomes), we investigated S-palmitoylation during synaptic activity. Induction of long-term potentiation (LTP) resulted in protein-specific palmitoylation changes without altering global levels. In hippocampal slices, synaptophysin and PSD95 displayed distinct temporal patterns of palmitoylation, influenced by LTP. Deacylation experiments using N-(tert-butyl)hydroxylamine (NtBuHA) demonstrated that protein S-palmitoylation is crucial for organizing neuronal spiking and enabling LTP, particularly in the stratum radiatum. Mass spectrometry of synaptoneurosomes revealed a palmitoylome including over 700 proteins, with stimulation-induced predominant depalmitoylation. Differentially palmitoylated proteins were associated with synaptic vesicle cycling, cytoskeletal dynamics, and neurotransmitter release. What is interesting is that synaptoneurosomes contained active palmitoylation machinery, supporting rapid, target-specific responses to NMDA receptor activation.

Conclusions

Temporal and protein-specific S-palmitoylation emerges as a vital mechanism for synaptic plasticity, contributing to neuronal network function and memory formation. These findings elucidate how palmitoylation acts as a dynamic regulator of synaptic activity and offer insights into its regulation. The study highlights the potential of targeting palmitoylation pathways for enhancing neuronal function.