Beta adrenergic receptors modulate spontaneous spatiotemporal activity patterns, and inter-cellular and inter-regional synchrony in hyper-excitable hippocampal circuits via PKA-dependent regulation of phosphorylated ERK.
Monday, Nov 14, 2011, 2:00 PM - 3:00 PM
, R. ROSENBAUM
, L. ABAD
, B. BODMANN
, S. CAO
, K. JOSIC
, J. ZIBURKUS
Dept Biol & Biochem,
Dept. of Mathematics,
Dept. of Earth and Atmospheric Sci., Univ. of Houston, HOUSTON, TX
Quantification of spatiotemporal dynamics of normal network activity and hyper-excitability is critical for decoding emergence of the pathological states. However, typical characteristics of emergent neural activity or their modulation by neuromodulators remain elusive. We investigated molecular, cellular, and network mechanisms of beta adrenergic receptor (β-AR) modulation of synchronized activity in rat hippocampal circuits. Synchronized epileptiform-like activity, interictal bursts (IBs) and ictal-like events (ILEs) were evoked by 4-Aminopyridine (4-AP, 50μM) or 0 Mg
(mM) ACSF; both models mimic pharmaco-resistant epilepsy. To dynamically characterize β-AR effects on spontaneous single cell and network activity, we performed concurrent fast voltage-sensitive dye imaging (500Hz-1.2KHz; UltimaL CMOS, Brain Vision) and electrophysiological (whole-cell and extracellular) recordings in juvenile rat (P21-30) hippocampal slices. Electro-optical analysis of the IBs and ILEs in single cells and the interconnected circuits showed that, in 4-AP, the IBs originated in the dentate gyrus/CA3 border and propagated to CA1. To modulate hyper-excitable circuit activity in 4-AP, we used β-AR agonist isoproterenol (ISO). ISO significantly reduced the spatial extent and propagation velocity of the IBs. This confinement is accompanied by increased variability and de-synchronization of pyramidal cell pairs and CA3-CA1regions. ISO also significantly suppressed activity in the low (1-20Hz) frequency ranges, in a region-specific manner. Durations of emergent prolonged ILEs in 4-AP and 0 Mg
were also significantly reduced by ISO. Molecular signaling mechanisms underlying ISO-specific changes in 4-AP were studied using Western blot analysis. We measured levels of phosphorylated extracellular signal-regulated kinase (pERK), located downstream of the protein kinase A (PKA). pERk levels were measured twenty minutes following application of 4-AP or 4-AP and ISO. Highest levels of pERK in the hippocampal slices were observed in 4-AP and were reduced by addition of ISO. PKA inhibitor H-89 (10µM) completely abolished the p-ERK activation in 4-AP. Additional tests indicated that downstream of PKA, another molecule, c-Raf differentially fine tuned pERK levels. Taken together our results suggest that ISO control of the cellular and network hyper-excitability and synchrony could be mediated via the fine tuning of pERK. Small molecules downstream of β-AR activation should be considered as potential therapeutic targets for pharmacoresistant epilepsy.
BETA ADRENERGIC RECEPTOR
[Authors]. [Abstract Title]. Program No. XXX.XX. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.
2011 Copyright by the Society for Neuroscience all rights reserved. Permission to republish any abstract or part of any abstract in any form must be obtained in writing by SfN office prior to publication.
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