Abstract
The four members of the LRRTM family (LRRTM1-4) are postsynaptic adhesion molecules essential for excitatory synapse development. They have also been implicated in neuropsychiatric diseases. Here, we focus on LRRTM3, showing that two distinct LRRTM3 variants generated by alternative splicing regulate LRRTM3 interaction with PSD-95, but not its excitatory synapse-promoting activity. Overexpression of either LRRTM3 variant increased excitatory synapse density in dentate gyrus (DG) granule neurons, whereas LRRTM3 knockdown decreased it. LRRTM3 also controlled activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner. Furthermore, Lrrtm3-knockout mice displayed specific alterations in excitatory synapse density, excitatory synaptic transmission and excitability in DG granule neurons but not in CA1 pyramidal neurons. Lastly, LRRTM3 required only specific splice variants of presynaptic neurexins for their synaptogenic activity. Collectively, our data highlight alternative splicing and differential presynaptic ligand utilization in the regulation of LRRTMs, revealing key regulatory mechanisms for excitatory synapse development.
Original language | English |
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Pages (from-to) | 808-822 |
Number of pages | 15 |
Journal | Cell Reports |
Volume | 14 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2016 Feb 2 |
Bibliographical note
Publisher Copyright:© 2016 The Authors.
Keywords
- Alternative splicing
- Dentate gyrus
- Excitatory synapse development
- Glypican
- LRRTM3
- LRRTM4
- Neurexin
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology