Abstract
Heterotetrameric glutamate receptors are essential for the development, function, and plasticity of spine synapses but how they are organized to achieve this is not known. Here we show that the nanoscale organization of glutamate receptors containing specific subunits define distinct subsynaptic features. Glutamate receptors containing GluA2 or GluN1 subunits establish nanomodular elements precisely positioned relative to Synaptotagmin-1 positive presynaptic release sites that scale with spine size. Glutamate receptors containing GluA1 or GluN2B specify features that exhibit flexibility: GluA1-subunit containing AMPARs are found in larger spines, while GluN2B-subunit containing NMDARs are enriched in the smallest spines with neither following a strict modular organization. Given that the precise positioning of distinct classes of glutamate receptors is linked to diverse events including cell death and synaptic plasticity, this unexpectedly robust synaptic nanoarchitecture provides a resilient system, where nanopositioned glutamate receptor heterotetramers define specific subsynaptic regions of individual spine synapses.
Highlights
Heterotetrameric glutamate receptors are essential for the development, function, and plasticity of spine synapses but how they are organized to achieve this is not known
GluA1-containing AMPARs are associated with the expression of synaptic plasticity, while GluN2 subunits in developing (GluN2B)-containing NMDARs are associated with the induction of plasticity and are thought to be found at more immature and smaller spines[3,5–8]
We demonstrate using STimulated Emission Depletion nanoscopy (STED) that the organization of NMDARs and AMPARs reflect the modular structure of pre- and postsynaptic scaffolding proteins, with the number of similar-sized clusters of these proteins scaling with spine size
Summary
Heterotetrameric glutamate receptors are essential for the development, function, and plasticity of spine synapses but how they are organized to achieve this is not known. We show that the nanoscale organization of glutamate receptors containing specific subunits define distinct subsynaptic features. Glutamate receptors containing GluA2 or GluN1 subunits establish nanomodular elements precisely positioned relative to Synaptotagmin-1 positive presynaptic release sites that scale with spine size. Given that the precise positioning of distinct classes of glutamate receptors is linked to diverse events including cell death and synaptic plasticity, this unexpectedly robust synaptic nanoarchitecture provides a resilient system, where nanopositioned glutamate receptor heterotetramers define specific subsynaptic regions of individual spine synapses. Despite the broad importance of subsynaptic location of glutamate receptor subunits for synaptic function, how glutamate receptor heterotetramers are organized at the nanoscale within spines is unclear. Heterotetrameric AMPARs containing the GluA1 subunit and heterotetrameric NMDARs with the GluN2B subunit do not show modules that scale with spine size Instead, they are preferentially localized to large and small spines, respectively, reflecting their function in synaptic plasticity and development. Our data describe robust organizational principles of essential components of synaptic transmission and plasticity
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