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New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity

Summary

This review explores how hallucinogens like ketamine and psilocybin produce long-lasting antidepressant effects by changing how brain cells communicate. The key mechanism involves special molecules called neurexins that sit at the connections between neurons and control whether those connections strengthen or weaken. By understanding and potentially targeting neurexins, scientists hope to develop new depression treatments that work longer and more effectively than current medications.

Background

Depression is a major psychiatric disorder affecting approximately 350 million people globally. Current antidepressant medications face challenges including low response rates, delayed effects, and short duration of efficacy. Recent interest has focused on ketamine and psilocybin as potential sustained antidepressants with longer-lasting therapeutic effects.

Objective

To examine the role of neurexins in regulating synaptic plasticity as a key mechanism underlying sustained antidepressant effects. The review aims to establish neurexins as critical molecular links between synaptic plasticity changes and sustained antidepressant outcomes, and to identify potential therapeutic targets for new drug development.

Results

Evidence demonstrates that synaptic plasticity changes are key downstream events in sustained antidepressant effects. Neurexins, presynaptic adhesion molecules, regulate synaptic plasticity through multiple mechanisms: protein expression levels, selective splicing at SS1-SS6 sites, epigenetic modifications, astrocyte interactions, positional redistribution, and protein structure changes. Multiple drugs including exercise, polyphenol metabolites, and various neuropeptides modulate neurexins and synaptic plasticity.

Conclusion

Neurexins represent a promising molecular target for understanding sustained antidepressant mechanisms. Focusing on neurexin-mediated regulation of synaptic plasticity provides a comprehensive framework for elucidating sustained antidepressant effects and identifying novel therapeutic strategies. This perspective opens new directions for drug development targeting neurexins and synaptic plasticity.
  • Published in:Cell Death Discovery,
  • Study Type:Review,
  • Source: PMID: 38693106, PMC: PMC11063156, DOI: 10.1038/s41420-024-01974-9
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