Acetylcholine‐induced seizure‐like activity and modified cholinergic gene expression in chronically epileptic rats
- 1 February 2008
- journal article
- Published by Wiley in European Journal of Neuroscience
- Vol. 27 (4), 965-975
- https://doi.org/10.1111/j.1460-9568.2008.06070.x
Abstract
The entorhinal cortex (EC) plays an important role in temporal lobe epilepsy. Under normal conditions, the enriched cholinergic innervation of the EC modulates local synchronized oscillatory activity; however, its role in epilepsy is unknown. Enhanced neuronal activation has been shown to induce transcriptional changes of key cholinergic genes and thus alter cholinergic responses. To examine cholinergic modulations in epileptic tissue we studied molecular and electrophysiological cholinergic responses in the EC of chronically epileptic rats following exposure to pilocarpine or kainic acid. We confirmed that while the total activity of the acetylcholine (ACh)-hydrolysing enzyme, acetylcholinesterase (AChE) was not altered, epileptic rats showed alternative splicing of AChE pre-mRNA transcripts, accompanied by a shift from membrane-bound AChE tetramers to soluble monomers. This was associated with increased sensitivity to ACh application: thus, in control rats, ACh (10–100 µm) induced slow (< 1Hz), periodic events confined to the EC; however, in epileptic rats, ACh evoked seconds-long seizure-like events with initial appearance in the EC, and frequent propagation to neighbouring cortical regions. ACh-induced seizure-like events could be completely blocked by the non-specific muscarinic antagonist, atropine, and were partially blocked by the muscarinic-1 receptor antagonist, pirenzepine; but were not affected by the non-specific nicotinic antagonist, mecamylamine. Epileptic rats presented reduced transcript levels of muscarinic receptors with no evidence of mRNA editing or altered mRNA levels for nicotinic ACh receptors. Our findings suggest that altered cholinergic modulation may initiate seizure events in the epileptic temporal cortex.Keywords
This publication has 66 references indexed in Scilit:
- Systematic identification of abundant A-to-I editing sites in the human transcriptomeNature Biotechnology, 2004
- “Epileptic Neurons” in Temporal Lobe EpilepsyBrain Pathology, 2002
- Animal Models of Limbic Epilepsies: What Can They Tell Us?Brain Pathology, 2002
- Optical Imaging Reveals Characteristic Seizure Onsets, Spread Patterns, and Propagation Velocities in Hippocampal–Entorhinal Cortex Slices of Juvenile RatsNeurobiology of Disease, 2000
- Potent depression of stimulus evoked field potential responses in the medial entorhinal cortex by serotoninBritish Journal of Pharmacology, 1999
- Competitive NMDA receptor antagonists do not block cholinergic kindling with carbacholEpilepsy Research, 1996
- Circuit Mechanisms of Seizures in the Pilocarpine Model of Chronic Epilepsy: Cell Loss and Mossy Fiber SproutingEpilepsia, 1993
- Dual regulation by G proteins of agonist‐dependent phosphorylation of muscarinic acetylcholine receptorsFEBS Letters, 1990
- Mossy fiber synaptic reorganization in the epileptic human temporal lobeAnnals of Neurology, 1989
- Molecular Properties Of The Muscarinic Acetylcholine ReceptorAnnual Review of Neuroscience, 1987