Neuronal Activity Induces Actin Polymerization in Dendritic Shafts, Regulating Intracellular AMPA Receptor Trafficking

Core Concepts

Neuronal activity induces actin polymerization in dendritic shafts, which confines AMPA receptor-containing vesicles near sites of stimulation, thereby promoting the delivery of AMPA receptors to synapses undergoing plasticity.

Abstract

The study investigates how neurons regulate the intracellular trafficking of AMPA receptors (AMPARs) during synaptic plasticity. The authors developed a method to label endogenous AMPAR GluA1 subunits with HaloTag in cultured rat hippocampal neurons, allowing them to track the motion of GluA1-containing vesicles using single-particle tracking and mathematical modeling. The key findings are: Inducing chemical long-term potentiation (cLTP) or structural LTP (sLTP) reduces the active transport and diffusion of GluA1 vesicles in the dendritic shaft, confining them near the sites of stimulation. The confinement of GluA1 vesicles is mediated by activity-induced actin polymerization in the dendritic shaft, which changes the rheological properties of the cytoplasm to inhibit vesicle motion. Actin polymerization in the dendritic shaft near the sites of stimulation also facilitates the myosin-mediated transport of GluA1 vesicles to exocytic sites, promoting the delivery of AMPARs to synapses undergoing plasticity. In summary, neurons utilize actin polymerization in dendritic shafts to increase the local concentration of AMPAR-containing vesicles near sites of neuronal activity, thereby enhancing the delivery of AMPARs to synapses undergoing plasticity.

Stats

Stimulating neurons with cLTP significantly increased the mean fluorescence intensity of JF549i-HTL-labeled GluA1-HT on neuronal membranes compared to unstimulated controls. The fraction of GluA1-HT vesicles undergoing active transport was significantly reduced in the dendritic shaft during cLTP induction compared to unstimulated controls. The diffusion coefficients of GluA1-HT vesicles were significantly reduced in the dendritic shaft during cLTP induction compared to unstimulated controls. The length of the F-actin network in the dendritic shaft, as measured by the skeleton length of the F-tractin signal, was significantly increased during cLTP induction compared to unstimulated controls. The fraction of GluA1-HT vesicles undergoing active transport was significantly reduced in the dendritic shaft regions with increased F-actin after sLTP, compared to regions without increased F-actin. The diffusion coefficients of GluA1-HT vesicles were significantly reduced in the dendritic shaft regions with increased F-actin after sLTP, compared to regions without increased F-actin. The number of GluA1-HT vesicles was significantly increased in the dendritic shaft regions with increased F-actin after sLTP, compared to regions without increased F-actin.

Quotes

"Neurons utilize F-actin to increase vesicular GluA1 reservoirs and promote exocytosis proximal to the sites of neuronal activity." "Actin polymerization in the dendritic shaft near the sites of stimulation facilitates myosin-mediated transport of GluA1-containing vesicles to exocytic sites."

Key Insights Distilled From

Plasticity-induced actin polymerization in the dendritic shaft regulates intracellular AMPA receptor trafficking

by Wong,V. C., ... at www.biorxiv.org 05-29-2022

https://www.biorxiv.org/content/10.1101/2022.05.29.493906v1

Deeper Inquiries

How might the activity-dependent confinement of AMPAR-containing vesicles in dendritic shafts be regulated by other cytoskeletal components or signaling pathways?

The activity-dependent confinement of AMPAR-containing vesicles in dendritic shafts could be regulated by other cytoskeletal components, such as microtubules. Microtubules are involved in the transport of vesicles within neurons, and their interactions with actin filaments could influence the confinement of AMPAR vesicles. Additionally, motor proteins like kinesins and dyneins, which transport cargo along microtubules, may play a role in regulating the movement and positioning of vesicles in response to neuronal activity. Signaling pathways involved in cytoskeletal dynamics, such as the Rho family of GTPases, could also modulate the actin polymerization that leads to vesicle confinement. For example, RhoA signaling can regulate actin polymerization through downstream effectors like ROCK, impacting the organization of the cytoskeleton and vesicle trafficking.

What are the potential functional consequences of restricting AMPAR trafficking to specific dendritic regions during synaptic plasticity?

Restricting AMPAR trafficking to specific dendritic regions during synaptic plasticity can have several functional consequences. Firstly, it allows for the precise targeting of AMPAR insertion to synapses that are undergoing potentiation, ensuring that the strengthening of synaptic connections occurs in a spatially controlled manner. This specificity in AMPAR trafficking can contribute to the input specificity of synaptic plasticity, where only synapses that are activated during potentiation receive additional AMPARs. Additionally, by concentrating AMPAR-containing vesicles near active synapses, the efficiency of synaptic transmission can be enhanced, leading to stronger and more reliable synaptic connections. This spatial regulation of AMPAR trafficking also enables the formation of functional microdomains within dendrites, where synaptic strength can be modulated in a localized fashion, contributing to the overall plasticity of neuronal circuits.

Could the mechanisms underlying activity-dependent AMPAR trafficking be leveraged to develop therapeutic interventions for neurological disorders characterized by synaptic dysfunction?

The mechanisms underlying activity-dependent AMPAR trafficking offer potential targets for therapeutic interventions in neurological disorders characterized by synaptic dysfunction. By understanding how neuronal activity regulates the trafficking and localization of AMPARs, novel strategies could be developed to modulate synaptic strength and plasticity in pathological conditions. For example, targeting the signaling pathways or cytoskeletal components involved in AMPAR trafficking could be a strategy to restore synaptic function in disorders where aberrant synaptic transmission is observed. Additionally, interventions that promote the confinement of AMPAR-containing vesicles to specific dendritic regions could be explored as a way to enhance synaptic connectivity and function in conditions associated with synaptic deficits. Overall, leveraging the mechanisms of activity-dependent AMPAR trafficking may offer new avenues for developing targeted therapies for neurological disorders affecting synaptic function.