Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons

Andrew Chay, Ilaria Zamparo, Andreas Koschinski, Manuela Zaccolo and Kim T Blackwell

PLOS Computational Biology, 2016, vol. 12, issue 2, 1-32

Abstract: Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.Author Summary: Noradrenaline is a stress related molecule that facilitates learning and memory when released in the hippocampus. The facilitation of memory is related to modulation of synaptic plasticity, but the mechanisms underlying this modulation are not well understood. We utilize a combination of live cell imaging and computational modeling to discover how noradrenergic receptor stimulation interacts with other molecules, such as calcium, required for synaptic plasticity and memory storage. Though prior work has shown that noradrenergic receptors and calcium interact synergistically to elevate intracellular second messengers when combined simultaneously, our results demonstrate that prior stimulation of noradrenergic receptors inhibits the elevation of intracellular second messengers. Our results further demonstrate that the inhibition may be caused by the noradrenergic receptor switching signaling pathways, thereby recruiting a different set of memory kinases. This switching represents a novel mechanism for recruiting molecules involved in synaptic plasticity and memory.

Date: 2016
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1004735

DOI: 10.1371/journal.pcbi.1004735

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