Slitrk2 controls excitatory synapse development via PDZ-mediated protein interactions.

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Slitrk proteins are cell-adhesion molecules regulating synapse development.
• Their role in postsynaptic intracellular signaling is poorly understood.
• Slitrk2's specific interactions with postsynaptic partners are unknown.

Purpose of the Study:

• Investigate Slitrk2's intracellular interactions.
• Identify molecular mechanisms of Slitrk2 in postsynaptic neurons.
• Determine the role of Slitrk2's PDZ-binding motif in synapse development.

Main Methods:

• Co-immunoprecipitation assays to detect protein interactions.
• In vitro binding assays using PDZ domain proteins.
• Analysis of synaptic targeting and synapse formation in cultured hippocampal neurons.
• In vivo complex formation studies.

Main Results:

• Slitrk2, but not other Slitrks, binds to PSD-95 and Shank3 via its C-terminal PDZ-binding motif (Ile-Ser-Glu-Leu).
• A single PDZ domain of Shank3 mediates binding to Slitrk2.
• Slitrk2 forms complexes with MAGUK family proteins, PSD-95, and Shank3 in vivo.
• The PDZ-binding motif of Slitrk2 is essential for excitatory synapse formation, transmission, and spine development in hippocampal CA1 neurons.

Conclusions:

• Slitrk2 utilizes a unique PDZ-binding motif to interact with postsynaptic scaffolds.
• This interaction mediates Slitrk2's function in excitatory synapse development and plasticity.
• A novel mechanism for isoform-specific Slitrk regulation of postsynaptic signaling is proposed.