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LRRTM3 Regulates Excitatory Synapse Development through Alternative Splicing and Neurexin Binding.

Ji Won Um1, Tae-Yong Choi2, Hyeyeon Kang3

  • 1Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; Department of Physiology and BK21 PLUS Project to Medical Sciences, Yonsei University College of Medicine, Seoul 120-751, Korea.

Cell Reports
|January 19, 2016
PubMed
Summary

Leucine-rich repeat transmembrane proteins 3 (LRRTM3) variants regulate excitatory synapse development. Alternative splicing of LRRTM3 impacts its interaction with PSD-95 and controls synapse density and AMPA receptor expression.

Keywords:
LRRTM3LRRTM4alternative splicingdentate gyrusexcitatory synapse developmentglypicanneurexin

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Synaptic Plasticity

Background:

  • Leucine-rich repeat transmembrane proteins (LRRTMs) are crucial for excitatory synapse formation.
  • LRRTMs are implicated in neuropsychiatric disorders.
  • LRRTM3's specific role and regulatory mechanisms remain incompletely understood.

Purpose of the Study:

  • To investigate the role of LRRTM3 variants generated by alternative splicing in excitatory synapse development.
  • To determine how LRRTM3 interacts with PSD-95 and influences synaptic activity.
  • To elucidate the presynaptic partners of LRRTM3.

Main Methods:

  • Analysis of LRRTM3 alternative splicing variants.
  • Overexpression and knockdown studies in dentate gyrus (DG) granule neurons.
  • Generation and analysis of Lrrtm3-knockout mice.
  • Investigation of LRRTM3 interactions with neurexin splice variants.

Main Results:

  • Two LRRTM3 splice variants differentially regulate interaction with PSD-95 but not synapse-promoting activity.
  • LRRTM3 overexpression increases, while knockdown decreases, excitatory synapse density in DG granule neurons.
  • LRRTM3 controls activity-regulated AMPA receptor surface expression in an alternative splicing-dependent manner.
  • Lrrtm3-knockout mice show altered DG granule neuron synapse density, transmission, and excitability, but not in CA1 pyramidal neurons.
  • LRRTM3 requires specific presynaptic neurexin splice variants for synaptogenic activity.

Conclusions:

  • Alternative splicing of LRRTM3 generates variants with distinct regulatory functions.
  • LRRTM3 plays a critical role in excitatory synapse development and function in a region-specific manner.
  • Differential utilization of presynaptic neurexin ligands is key to LRRTM3-mediated synaptogenesis.