Colocalization of Protein Kinase A with Adenylyl Cyclase Enhances Protein Kinase A Activity during Induction of Long-Lasting Long-Term-Potentiation

Myungsook Kim,Robbert Havekes,Alan Jung Park,Rodrigo Freire Oliveira,Ted Abel,Andrew Chay,Leonardo Antonio Guercio,Kim T Blackwell,Lyle J Graham

doi:10.1371/journal.pcbi.1002084

Abstract

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring.

Highlights

Synaptic plasticity, the activity-dependent change in the strength of neuronal connections, is a cellular mechanism proposed to underlie memory storage
Previous experiments showed that anchoring of protein kinase A (PKA) was necessary for long term potentiation (LTP) induced with four trains of 100 Hz stimulation applied with a 300 s interval, but they did not demonstrate whether PKA needs to be anchored near its target molecules, such as the AMPA receptor GluR1 subunit, or near a source of activator molecules, such as adenylyl cyclase that produces cAMP
To evaluate which of these two possible functions of PKA anchoring in four-train LTP is more important, the signaling pathways that underlie synaptic plasticity in hippocampal CA1 pyramidal neurons (Figure 1A) were implemented in NeuroRD [15], software for simulating stochastic reaction diffusion systems, in the morphology of a dendrite with spines (Figure 1B)

Summary

Introduction

The activity-dependent change in the strength of neuronal connections, is a cellular mechanism proposed to underlie memory storage. One type of synaptic plasticity is long term potentiation (LTP), which displays physiological properties that are highly suggestive of information storage. Because of the role of the hippocampus in memory, LTP in the hippocampus is studied as a model of cellular properties underlying memory [1]. The induction of long-lasting forms of LTP requires interaction among calcium-activated pathways and metabotropic-receptor-activated pathways, but the interactions among these pathways depend on the extent to which signals are spatially restricted to subcellular compartments. A PKA-dependent form of hippocampal LTP requires PKA activation, and the appropriate localization of PKA [4,5]

Methods

Results

Conclusion