Aim: 

An essential aspect for neurotransmitter receptors function is the appropriate localization and cell surface expression. Differential subunit trafficking, targeting and assembly tightly regulates the physiological roles of glutamate receptors and these events are controlled through interactions with proteins that bind to cytoplasmic domains of receptor subunits. Glutamate is the major excitatory neurotransmitter in the mammalian brain and it activates three types of ionotropic receptors NMDA, AMPA, and kainate (KARs). The knowledge of these aspects from KARs lags far behind that for other receptors, and only lately has our understanding of KARs trafficking and targeting grown.

Methods: 

Biochemical experiments in transfected cells and brain tissue. Immunocytochemical methods in cultured neurons and transfected cells. Electrophysiology in hippocampal slices.

Results: 

We have found that SNAP25 is critical for the synaptic removal of KARs, specifically acting via KA2 subunits. SNAP25 co-immunoprecipitates with protein complexes containing PICK1, GRIP1 and KA2 and co-localizes with KA2 in both hippocampal neurons and transfected HEK293 cells. In mouse hippocampal slices, purified SNAP25 antibodies and inhibitory peptides caused a KA2-dependent run-up of KARs-mediated EPSC recorded from CA3 pyramidal neurons when included in the patch pipette and prevented activity-dependent long-term depression of KAR-mediated synaptic responses (KAR-LTD). As KAR-LTD, SNAP25/PICK1/KA2 interactions are dynamically regulated by protein kinase C.

Conclusion: 

This process provides a mechanism for both rapid and chronic changes in the number of synaptic KARs and indicates an unprecedented role of SNAP25 in endocytosis of glutamate receptors and synaptic plasticity.

Supported by BFU 2006-07138 and a Consolider Programme (CSD2007-0023).