Summary: Glutamate is released in two distinct phases at hippocampal synapses: first near AMPA-type receptors to transmit the immediate signal, and then near NMDA-type receptors to trigger the molecular switch that enables synaptic plasticity.
Source: Marine Biological Laboratory
Glutamate is the primary excitatory neurotransmitter in the brain, central to neuronal communication, learning, and memory through the mechanism known as synaptic plasticity.
Glutamate plays a critical role in normal brain function and is also implicated in pathological conditions: after stroke, traumatic brain injury, or during neurodegenerative disease, excess extracellular glutamate can become neurotoxic and contribute to cell damage or death.
Shigeki Watanabe of Johns Hopkins University School of Medicine, a recurring faculty researcher in the Marine Biological Laboratory (MBL) Neurobiology course, has been investigating the spatial and temporal patterns of glutamate release that enable precise neuronal signaling. Building on earlier work describing how synaptic vesicles release glutamate after an action potential, Watanabe and colleagues have now published a follow-up study that clarifies how release timing and location align with postsynaptic receptor types to promote plasticity.
“With this paper, we uncover how signals are transmitted across synapses to turn on the switch for plasticity,” Watanabe explains. The team shows that glutamate release is organized into a fast, synchronous phase and a delayed, asynchronous phase. The synchronous release occurs preferentially near AMPA-type glutamate receptors, efficiently conveying the initial excitatory signal to the neighboring neuron. The asynchronous release follows immediately and occurs near NMDA-type receptors, serving to activate the NMDA receptors that mediate calcium influx and downstream signaling necessary for synaptic plasticity.
The research integrated experimental work performed in part within the MBL Neurobiology course. Watanabe notes the long-running collaborative nature of the effort: the project began with course students in 2018, continued with additional students in 2019, and included contributions from a teaching assistant who became first author. This hands-on training environment helped support the detailed imaging and analysis required to map release sites relative to receptor clusters.
Key findings
– Release occurs in two temporally distinct phases after an action potential: synchronous (fast) and asynchronous (delayed).
– These phases are not randomly distributed across the active zone. Instead, synchronous release sites are biased toward locations aligned with AMPA receptor clusters, while asynchronous release sites are enriched near NMDA receptor clusters.
– Computational simulations performed by the team indicate that this precise spatial and temporal arrangement maximizes membrane depolarization through AMPA receptors. That depolarization relieves the magnesium block in NMDA receptor channels, allowing stronger NMDA receptor activation during the asynchronous phase. Efficient NMDA activation is a critical step for calcium-dependent processes that underlie synaptic strengthening and plasticity.
Together, the experimental mapping and modeling data suggest that the synaptic release machinery is organized to ensure that the two receptor classes are engaged in the optimal sequence: AMPA receptors initiate rapid depolarization, and NMDA receptors are subsequently positioned to detect that depolarization and trigger plasticity-related signaling.
Study context and contributions
This study was conducted with contributions from MBL Neurobiology course participants and collaborators, reflecting a blend of teaching and research. The multidisciplinary effort combined high-resolution structural analysis of release sites, receptor localization, and computational simulations to connect spatial organization with functional consequences for synaptic signaling and plasticity.
Source: Marine Biological Laboratory
Contact: Diana Kenney – Marine Biological Laboratory
Image: The image is in the public domain
Original Research: Open access. “Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses” by Shuo Li, Sumana Raychaudhuri, Stephen Alexander Lee, Marisa M. Brockmann, Jing Wang, Grant Kusick, Christine Prater, Sarah Syed, Hanieh Falahati, Raul Ramos, Tomas M. Bartol, Eric Hosy & Shigeki Watanabe. Published in Nature Communications.
Abstract
Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses
Neurotransmitter is released both synchronously and asynchronously following an action potential. Recent work indicates these two phases originate from spatially segregated release sites within the active zone, with asynchronous release sites enriched near the center of mouse hippocampal synapses. The present study demonstrates that synchronous and asynchronous release sites align with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this spatial and temporal arrangement produces maximal membrane depolarization via AMPA receptors, which relieves the magnesium block on NMDA receptors and permits stronger NMDA activation. These results suggest that release site organization is optimized to activate NMDA receptors efficiently and thereby support mechanisms of synaptic plasticity.