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Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking
Jason Aoto1, David C Martinelli, Robert C Malenka
1Department of Molecular and Cellular Physiology, Stanford University Medical School, 265 Campus Drive, CA 94305-5453, USA.
Cell
|July 6, 2013
Summary
Neurexin alternative splicing controls postsynaptic AMPA receptor levels and trafficking. This reveals a novel mechanism for regulating synaptic strength and plasticity, impacting conditions like autism and schizophrenia.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neurexins are crucial presynaptic cell adhesion molecules implicated in neurological disorders such as schizophrenia and autism.
- Neurexin alternative splicing is extensive and its physiological significance remains incompletely understood.
- Sequence #4 (SS4) of neurexin-3 is highly regulated and influences interactions with postsynaptic ligands.
Purpose of the Study:
- To investigate the physiological role of neurexin-3 alternative splicing, specifically the inclusion of SS4.
- To determine how SS4 inclusion affects synaptic function and plasticity.
Main Methods:
- Generation of knockin mice with conditional inclusion/excision of neurexin-3 SS4.
- Analysis of postsynaptic AMPA and NMDA receptor levels.
- Assessment of AMPA receptor endocytosis and recruitment during long-term potentiation (LTP).
Main Results:
- Constitutive inclusion of neurexin-3 SS4 decreased postsynaptic AMPA receptor levels.
- SS4 inclusion enhanced postsynaptic AMPA receptor endocytosis.
- Neurexin-3 SS4 abrogated postsynaptic AMPA receptor recruitment during NMDA receptor-dependent LTP.
- Phenotypes were rescued by selective excision of SS4.
Conclusions:
- Alternative splicing of presynaptic neurexin-3 directly controls postsynaptic AMPA receptor trafficking.
- This highlights an unexpected mechanism of trans-synaptic regulation impacting synaptic strength and plasticity.
- Findings provide insights into the molecular basis of neurological disorders linked to neurexin dysfunction.
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