SAP97 directs NMDA receptor spine targeting and synaptic plasticity

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• SAP97 is a scaffold protein crucial for trafficking and localizing NMDA- and AMPA-type glutamate receptors at synapses.
• Alternative splicing generates αSAP97 and βSAP97 isoforms with distinct roles in subsynaptic localization of AMPA receptor subunits.

Purpose of the Study:

• To investigate how SAP97 isoforms (αSAP97 and βSAP97) influence the mechanisms of long-term potentiation (LTP) and long-term depression (LTD).
• To determine the specific roles of αSAP97 and βSAP97 in regulating glutamate receptor distribution and synaptic plasticity.

Main Methods:

• Electrophysiological recordings from synaptically coupled hippocampal neurons.
• Live imaging of αSAP97 and βSAP97.
• Analysis of surface pools of AMPA and NMDA receptors.
• Knockdown of βSAP97 to assess endogenous function.

Main Results:

• Both αSAP97 and βSAP97 impair LTP and enhance LTD through distinct, isoform-specific mechanisms.
• αSAP97 enhances postsynaptic AMPA receptor levels, occluding LTP, while βSAP97 reduces NMDA receptor synaptic localization, blocking LTP.
• αSAP97 regulates synaptic AMPA receptors, whereas βSAP97 controls extrasynaptic pools of both AMPA and NMDA receptors.

Conclusions:

• SAP97 isoforms differentially control synaptic plasticity by modulating the distribution of glutamate receptors between synaptic and extrasynaptic sites.
• Endogenous βSAP97 restricts glutamate receptor expression at excitatory synapses, influencing the capacity for synaptic plasticity.