Physiological learning involves intrasynaptic reorganization of GluA1-containing AMPA receptors
- 1Institute of Science and Technology Austria (ISTA)
Abstract
Learning and memory formation depend on persistent modifications of excitatory synaptic transmission in the hippocampus through changes in AMPA receptor (AMPAR) content and properties at potentiated synapses. However, directly demonstrating such changes after physiological, behavior-driven learning in the intact brain has remained technically difficult. Using SDS-digested freeze-fracture replica labeling (SDS-FRL), we examined the density and nanoscale localization of AMPAR subunits GluA1, GluA2, and GluA3 in the mouse hippocampal CA1 pyramidal cells. GluA2 density was higher than GluA1 and GluA3 densities at both synaptic and extrasynaptic sites, consistent with previous studies showing that AMPARs in CA1 pyramidal cells mostly contain GluA2. The extrasynaptic density of GluA3 was substantially lower than those of GluA1 and GluA2, pointing to distinct trafficking mechanisms. GluA1- and GluA2-containing receptors were enriched at synaptic peripheries, whereas GluA3 was more centrally localized and clustered, a subunit-specific intrasynaptic organization consistent with differential roles in plasticity. To investigate learning-induced reorganization, we combined the inhibitory avoidance, hippocampus-dependent contextual learning paradigm with SDS-FRL in the CA1 stratum radiatum. Learning induced a selective increase in synaptic GluA1 density accompanied by a concurrent decrease in GluA2 density, consistent with a compositional shift toward higher-conductance GluA1-containing receptors, specifically in the proximal CA1 area. Strikingly, we found a redistribution of GluA1 from the synaptic periphery toward the center, accompanied by increased clustering. These findings reveal intrasynaptic receptor redistribution alongside subunit composition change, a nanoscale molecular signature at CA3-CA1 synapses, which may constitute a mechanism of hippocampal memory formation in physiological learning.
Related
- Melatonin modulates habituation learning via the convergent action of two MT1-type receptors.
- YieldLearn: An interpretable machine-learning pipeline for estimating yield-related traits based on physiological indicators
- An interpretable multimodal deep learning model for physiological stress detection
- Non‑monotonic reorganization of cortical neuron firing despite ongoing delta‑dominated activity
- Movement mechanisms explain current animal density patterns and predict their reorganization under global change
BibTeX
@misc{jevtic2026physiological,
title = {{Physiological learning involves intrasynaptic reorganization of GluA1-containing AMPA receptors}},
author = {M. Jevtic and E. Hollergschwandtner and B. Kartono and Y. Sugiyama and L. Strnadova and R. Ramesh and Y. Fukazawa and M. Itakura and R. Shigemoto},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.22.760928},
url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760928v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Physiological learning involves intrasynaptic reorganization of GluA1-containing AMPA receptors
AU - M. Jevtic
AU - E. Hollergschwandtner
AU - B. Kartono
AU - Y. Sugiyama
AU - L. Strnadova
AU - R. Ramesh
AU - Y. Fukazawa
AU - M. Itakura
AU - R. Shigemoto
PY - 2026
DA - 2026/10/22
PB - bioRxiv
DO - 10.64898/2026.10.22.760928
UR - https://www.biorxiv.org/content/10.64898/2026.10.22.760928v1
AB - Learning and memory formation depend on persistent modifications of excitatory synaptic transmission in the hippocampus through changes in AMPA receptor (AMPAR) content and properties at potentiated synapses. However, directly demonstrating such changes after physiological, behavior-driven learning in the intact brain has remained technically difficult. Using SDS-digested freeze-fracture replica labeling (SDS-FRL), we examined the density and nanoscale localization of AMPAR subunits GluA1, GluA2, and GluA3 in the mouse hippocampal CA1 pyramidal cells. GluA2 density was higher than GluA1 and GluA3 densities at both synaptic and extrasynaptic sites, consistent with previous studies showing that AMPARs in CA1 pyramidal cells mostly contain GluA2. The extrasynaptic density of GluA3 was substantially lower than those of GluA1 and GluA2, pointing to distinct trafficking mechanisms. GluA1- and GluA2-containing receptors were enriched at synaptic peripheries, whereas GluA3 was more centrally localized and clustered, a subunit-specific intrasynaptic organization consistent with differential roles in plasticity. To investigate learning-induced reorganization, we combined the inhibitory avoidance, hippocampus-dependent contextual learning paradigm with SDS-FRL in the CA1 stratum radiatum. Learning induced a selective increase in synaptic GluA1 density accompanied by a concurrent decrease in GluA2 density, consistent with a compositional shift toward higher-conductance GluA1-containing receptors, specifically in the proximal CA1 area. Strikingly, we found a redistribution of GluA1 from the synaptic periphery toward the center, accompanied by increased clustering. These findings reveal intrasynaptic receptor redistribution alongside subunit composition change, a nanoscale molecular signature at CA3-CA1 synapses, which may constitute a mechanism of hippocampal memory formation in physiological learning.
ER -