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      Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

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      PLoS Computational Biology
      Public Library of Science

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          Abstract

          Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity.

          Author Summary

          The striatum is a part of the basal ganglia which plays a role in addiction and reward learning. Its importance is underscored by pathologies such as Parkinson's disease and Huntington's disease in which degeneration of the dopamine inputs to the striatum or degeneration of neurons in the striatum, respectively, produces motor dysfunction. Dopamine in the striatum activates cascades of signaling molecules, ultimately producing an activity dependent change in the strength of connections between neurons. However, the dispersive movement of signaling molecules seems incompatible with the strengthening of specific subsets of connections, which is required for formation of distinct memories. Anchoring proteins, which restrict molecules to particular compartments within the neuron, are proposed to achieve specificity. We develop a reaction-diffusion model of dopamine activated signaling pathways to explore mechanisms whereby anchoring proteins can produce specificity. We use an efficient Monte-Carlo simulator to implement the cascades of signaling molecules in a neuronal dendrite with multiple dendritic spines. Simulations demonstrate that spatial specificity requires both anchoring proteins and inactivation mechanisms that limit the diffusion of signaling molecules.

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          Most cited references96

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          AKAP signalling complexes: focal points in space and time.

          Multiprotein signalling networks create focal points of enzyme activity that disseminate the intracellular action of many hormones and neurotransmitters. Accordingly, the spatio-temporal activation of protein kinases and phosphatases is an important factor in controlling where and when phosphorylation events occur. Anchoring proteins provide a molecular framework that orients these enzymes towards selected substrates. A-kinase anchoring proteins (AKAPs) are signal-organizing molecules that compartmentalize various enzymes that are regulated by second messengers.
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            Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity.

            Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.
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              Locally dynamic synaptic learning rules in pyramidal neuron dendrites.

              Long-term potentiation (LTP) of synaptic transmission underlies aspects of learning and memory. LTP is input-specific at the level of individual synapses, but neural network models predict interactions between plasticity at nearby synapses. Here we show in mouse hippocampal pyramidal cells that LTP at individual synapses reduces the threshold for potentiation at neighbouring synapses. After input-specific LTP induction by two-photon glutamate uncaging or by synaptic stimulation, subthreshold stimuli, which by themselves were too weak to trigger LTP, caused robust LTP and spine enlargement at neighbouring spines. Furthermore, LTP induction broadened the presynaptic-postsynaptic spike interval for spike-timing-dependent LTP within a dendritic neighbourhood. The reduction in the threshold for LTP induction lasted approximately 10 min and spread over approximately 10 microm of dendrite. These local interactions between neighbouring synapses support clustered plasticity models of memory storage and could allow for the binding of behaviourally linked information on the same dendritic branch.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                February 2012
                February 2012
                9 February 2012
                : 8
                : 2
                Affiliations
                [1]The Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America
                Indiana University, United States of America
                Author notes

                Conceived and designed the experiments: RFO KTB. Performed the experiments: RFO MSK. Analyzed the data: RFO MSK KTB. Wrote the paper: RFO KTB.

                Article
                PCOMPBIOL-D-11-01087
                10.1371/journal.pcbi.1002383
                3276550
                22346744
                e5c2b7db-72f5-4662-980b-ca58f4809fef
                Oliveira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 19
                Categories
                Research Article
                Biology
                Computational Biology
                Neuroscience

                Quantitative & Systems biology
                Quantitative & Systems biology

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