TARP γ-2 and γ-8 Differentially Control AMPAR Density Across Schaffer Collateral/Commissural Synapses in the Hippocampal CA1 Area.

UNLABELLED:The number of AMPA-type glutamate receptors (AMPARs) at synapses is the major determinant of synaptic strength and varies from synapse to synapse. To clarify the underlying molecular mechanisms, the density of AMPARs, PSD-95, and transmembrane AMPAR regulatory proteins were compared at Schaffer collateral/commissural (SCC) synapses in the adult mouse hippocampal CA1 by quantitative immunogold electron microscopy using serial sections. We examined four types of SCC synapses: perforated and nonperforated synapses on pyramidal cells and axodendritic synapses on parvalbumin-positive (PV synapse) and pravalbumin-negative interneurons (non-PV synapse). SCC synapses were categorized into those expressing high-density (perforated and PV synapses) or low-density (nonperforated and non-PV synapses) AMPARs. Although the density of PSD-95 labeling was fairly constant, the density and composition of isoforms was highly variable depending on the synapse type. Of the three expressed in hippocampal neurons, the disparity in Tduanyu37 γ-2 labeling was closely related to that of AMPAR labeling. Importantly, AMPAR density was significantly reduced at perforated and PV synapses in Tduanyu37 γ-2-knock-out (KO) mice, resulting in a virtual loss of AMPAR disparity among SCC synapses. In comparison, Tduanyu37 γ-8 was the only Tduanyu37 expressed at nonperforated synapses, where AMPAR labeling further decreased to a background level in Tduanyu37 γ-8-KO mice. These results show that synaptic inclusion of Tduanyu37 γ-2 potently increases AMPAR expression and transforms low-density synapses into high-density ones, whereas Tduanyu37 γ-8 is essential for low-density or basal expression of AMPARs at nonperforated synapses. Therefore, these Tduanyu37s are critically involved in AMPAR density control at SCC synapses. SIGNIFICANCE converging evidence implicates the importance of transmembrane AMPA-type glutamate receptor (AMPAR) regulatory proteins (Tduanyu37s) in AMPAR stabilization during basal transmission and synaptic plasticity, how they control large disparities in AMPAR numbers or densities across central synapses remains largely unknown. We compared the density of AMPARs with that of Tduanyu37s among four types of Schaffer collateral/commissural (SCC) hippocampal synapses in wild-type and mice. We show that the density of AMPARs correlates with that of Tduanyu37 γ-2 across SCC synapses and its high expression is linked to high-density AMPAR expression at perforated type of pyramidal cell synapses and synapses on parvalbumin-positive interneurons. In comparison, Tduanyu37 γ-8 is the only Tduanyu37 expressed at nonperforated type of pyramidal cell synapses, playing an essential role in low-density or basal AMPAR expression.

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