| Abstract No.: | A-B1043 |
| Country: | Canada |
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| Title: | MODULATION OF LONG-TERM POTENTIATION BY NORADRENERGIC AND MUSCARINIC RECEPTORS |
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| Authors/Affiliations: | 1 Steven Connor*; 1 Peter Nguyen;
1 University of Alberta, Edmonton, AB, Canada
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| Content: | Previous research indicates that synaptic plasticity could provide a cellular mechanism for learning and memory. Long-term potentiation (LTP), an activity dependent enhancement of synaptic strength that lasts for several hours or days, can be induced in the hippocampus, a structure critical for learning and memory. LTP induction in the hippocampus is likely to require molecular changes which can be regulated by neuromodulators. Previous research has shown that co-activation of beta-adrenergic (beta-AR) and muscarinic receptors (MR) paired with theta frequency (5Hz,5sec) stimulation induces persistent LTP in the hippocampal CA1 region, which is
dependent upon mitogen-activated protein kinase (MAPK) activation (Watabe et al., 2003).
Objectives:
We sought to further characterize the intracellular mechanisms engaged by co-activation of beta-adrenergic and muscarinic receptor activation and to determine if the coincident activation of these receptors leads to a synergistic effect on translational regulation.
Materials and Methods:
Field excitatory postsynaptic potentials (fEPSPs) were recorded from C57BL/6 mouse hippocampal slices, area CA1. 400μM transverse hippocampal slices were maintained in an interface chamber at 28°C and perfused (1-2 mL/min) with artificial cerebrospinal fluid (ACSF). fEPSPs were recorded using Clampex 7 software. All drugs were bath
applied.
Drugs: beta-adrenergic receptor agonist ISO[R(-)-isoproterenol(+)-bitartrate, 200nM; beta-adrenergic receptor antagonist propranolol [(±)-propranolol hydrochloride, 50 µM; cAMP-dependent Protein Kinase A inhibitor, PKI, 10 µM; muscarinic receptor agonist, carbachol, 200nM; muscarinic receptor antagonist, atropine; M1 muscarinic antagonist, pirenzepine, 20µM; protein synthesis inhibitor, anisomycin, 40 µM; transcriptional inhibitor, actinomycin-D; 25 µM.
Results:
We found that co-application of the beta-AR agonist, isoproterenol, and the muscarinic agonist, carbachol (CAR) allows a low-frequency stimulation protocol (5Hz,5sec) which does not normally induce LTP, to induce long-lasting (>2hrs) LTP. This form of LTP is dependent upon NMDARs, beta1-ARs, and M1 muscarinic receptors. Additionally,
cAMP-dependent protein kinase (PKA) is required for maintenance of this form of LTP. As PKA pathways have been shown to regulate translation initiation, we wanted to determine if this form of LTP was dependent upon protein synthesis. Application of the translation inhibitor, anisomycin, blocked the maintenance of ISO+CAR-dependent
LTP. However, blocking transcription with actinomycin-D had no effect
on this form of LTP.
Conclusions:
Our results suggest that co-activation of beta-ARs, and M1 muscarinic receptors paired with LFS can induce LTP through activation of a PKA-dependent pathway. Additionally, the ISO+CAR+5Hz-induced LTP depends upon translation but is independent of transcription, suggesting that beta-AR and muscarinic receptors may act synergistically
to regulate protein synthesis.
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