Abstract
AMPA receptors–mediators of fast, excitatory transmission and synaptic plasticity in the brain–achieve great functional diversity through interaction with different auxiliary subunits, which alter both the trafficking and biophysical properties of these receptors. In the past several years an abundance of new AMPA receptor auxiliary subunits have been identified, adding astounding variety to the proteins known to directly bind and modulate AMPA receptors. SynDIG1 was recently identified as a novel AMPA receptor interacting protein that directly binds to the AMPA receptor subunit GluA2 in heterologous cells. Functionally, SynDIG1 was found to regulate the strength and density of AMPA receptor containing synapses in hippocampal neurons, though the way in which SynDIG1 exerts these effects remains unknown. Here, we aimed to determine if SynDIG1 acts as a traditional auxiliary subunit, directly regulating the function and localization of AMPA receptors in the rat hippocampus. We find that, unlike any of the previously characterized AMPA receptor auxiliary subunits, SynDIG1 expression does not impact AMPA receptor gating, pharmacology, or surface trafficking. Rather, we show that SynDIG1 regulates the number of functional excitatory synapses, altering both AMPA and NMDA receptor mediated transmission. Our findings suggest that SynDIG1 is not a typical auxiliary subunit to AMPA receptors, but instead is a protein critical to excitatory synaptogenesis.
Highlights
The AMPA-type ionotropic glutamate receptors (AMPARs) underlie fast, excitatory synaptic transmission and plasticity in the brain [1] [2]
We recorded current-voltage relationships from outside-out patches obtained from HEK cells expressing GluA1 and GluA2 alone or in combination with Synapse Differentiation Induced Gene 1 (SynDIG1) and found that SynDIG1 expression did not result in a change in AMPAR rectification, indicating that SynDIG1 expression does not affect intracellular polyamine affinity (Figure 1C)
Inward rectification, desensitization and deactivation rates, we found that SynDIG1 does not behave like known AMPAR auxiliary subunits by regulating receptor gating or pharmacology
Summary
The AMPA-type ionotropic glutamate receptors (AMPARs) underlie fast, excitatory synaptic transmission and plasticity in the brain [1] [2]. The functional diversity of these tetrameric receptors was thought to originate solely from their subunit composition, which confer different biophysical properties and roles in synaptic transmission [3] [4]. AMPAR auxiliary subunits are typically defined as transmembrane proteins that bind directly to AMPARs, and, similar to other ion channel auxiliary subunits, alter ER trafficking, surface localization, subcellular targeting, and modulation of receptor biophysical properties [5] [6] [7] [8]. Overexpression of SynDIG1 in dissociated hippocampal neurons led to a dramatic increase in miniature excitatory postsynaptic current (mEPSC) amplitude and frequency, along with increases in the density and size of AMPAR-containing synaptic puncta. ShRNA-mediated knockdown of SynDIG1 had the opposite effect, greatly reducing mEPSC frequency and amplitude, while decreasing the density and size of AMPAR-containing synaptic puncta. Owing to its binding to AMPARs, it is possible that SynDIG1 alters AMPARmediated synaptic transmission by direct modification of channel gating properties
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