Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Excitatory synapses display functional plasticity, primarily through alterations in synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) numbers.
• The precise mechanisms governing AMPAR recruitment to synapses remain largely unelucidated.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the synaptic targeting of AMPARs.
• To identify the key proteins involved in regulating AMPARs at excitatory synapses.

Main Methods:

• Utilized hippocampal slice cultures for studying synaptic function.
• Employed biolistic gene transfection techniques to manipulate protein expression levels.
• Investigated protein-protein interactions using molecular binding assays and mutational analyses.

Main Results:

• Demonstrated that the first two PDZ domains of postsynaptic density protein of 95 kDa (PSD-95) directly bind to stargazin, mediating AMPAR localization to synapses.
• Showed that elevated synaptic PSD-95 levels increase synaptic AMPARs without affecting total surface AMPARs.
• Found that stargazin overexpression increases extra-synaptic AMPARs but does not alter synaptic currents if PSD-95 levels are constant.
• Confirmed the critical role of direct PSD-95 and stargazin interaction in determining synaptic AMPAR numbers via compensatory mutations.

Conclusions:

• Direct interaction between PSD-95 and stargazin is essential for recruiting AMPARs to synapses.
• This interaction plays a pivotal role in regulating the number of synaptic AMPARs and consequently, synaptic plasticity.
• Findings provide a molecular basis for understanding how excitatory synapse function is modulated.