Cholinergic Dysfunction in Temporal Lobe Epilepsy

Friedman, Alon; Behrens, Christoph; Heinemann, Uwe

doi:10.1111/j.1528-1167.2007.01300.x

Cited by 77 publications

(56 citation statements)

References 51 publications

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“…This septohippocampal pathway plays a critical role in epileptogenesis, especially in temporal lobe epilepsy (TLE) (Friedman et al, 2007). Muscarinic stimulation is effective in generating limbic seizures and injection of cholinergic agents is used as a model for TLE (Lothman et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons

et al. 2011

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In cultured hippocampal neurons, transient receptor potential 5 (TRPC5) channels are translocated and inserted into plasma membranes of hippocampal neurons to generate nonselective cation (NSC) currents. We investigated whether TRPC5 channel translocation also contributes to the generation of NSC currents underlying the afterdepolarizations and plateau potentials (PPs) in hippocampal pyramidal cells that are induced by muscarinic receptor activation. Using a biotinylation assay to quantify the change in surface membrane proteins in acute hippocampal slices, we found that muscarinic stimulation significantly enhanced the levels of TRPC5 protein on the membrane surface but not those of TRPC1 or TRPC4 channels. We then investigated the pharmacological sensitivity of the cation current observed during muscarinic stimulation to determine if a component could be due to TRPC5 channels. The TRPC channel antagonists 2-APB and SKF96365 strongly depressed the generation of PPs, the underlying tail currents (I(tail)) and the associated dendritic Ca(2+) influx induced by muscarinic receptor activation in pyramidal neurons. High intracellular concentrations of ATP, which specifically inhibit TRPC5 channels, depressed I(tail). In addition, pretreatment with the calmodulin (CaM) inhibitor W-7, which depresses recombinant TRPC5 currents, inhibited both the cation current (I(tail)) and the surface insertion of TRPC5 channels. Finally, the phosphatidylinositide 3-kinase (PI(3)K) inhibitor wortmannin, which blocks translocation of TRPC5 channels in cell culture, also inhibited both the I(tail) and the surface insertion of TRPC5 channels. Therefore, we conclude that insertion of TRPC5 channels contributes to the generation of the prolonged afterdepolarizations following muscarinic stimulation. This altered plasma membrane expression of TRPC5 channels in pyramidal neurons may play an important role in the generation of prolonged neuronal depolarization and bursting during the epileptiform seizure discharges of epilepsy.

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Section: Discussionmentioning

confidence: 99%

Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons

et al. 2011

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“…Specifically, while K M appears to play only a limited role, K IR seems to be a major regulator of CCh-induced events. Further studies are needed to investigate whether these currents might be useful pharmacological targets to counteract muscarinic-dependent mechanisms possibly involved in TLE (Friedman et al, 2007). CCh-induced synchronized field oscillations in EC.…”

Section: Conclusive Remarksmentioning

confidence: 99%

Involvement of inward rectifier and M-type currents in carbachol-induced epileptiform synchronization

et al. 2011

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Exposure to cholinergic agonists is a widely used paradigm to induce epileptogenesis in vivo and synchronous activity in brain slices maintained in vitro. However, the mechanisms underlying these effects remain unclear. Here, we used field potential recordings from the lateral entorhinal cortex in horizontal rat brain slices to explore whether two different K + currents regulated by muscarinic receptor activation, the inward rectifier (K IR ) and the M-type (K M ) currents, have a role in carbachol (CCh)-induced field activity, a prototypical model of cholinergic-dependent epileptiform synchronization. To establish whether K IR or K M blockade could replicate CCh effects, we exposed slices to blockers of these currents in the absence of CCh. K IR channel blockade with micromolar Ba 2+ concentrations induced interictal-like events with duration and frequency that were lower than those observed with CCh; by contrast, the K M blocker linopirdine was ineffective. Pre-treatment with Ba 2+ or linopirdine increased the duration of epileptiform discharges induced by subsequent application of CCh. Baclofen, a GABA B receptor agonist that activates K IR , abolished CCh-induced field oscillations, an effect that was abrogated by the GABA B receptor antagonist CGP 55845, and prevented by Ba 2+ . Finally, when applied after CCh, the K M activators flupirtine and retigabine shifted leftward the cumulative distribution of CChinduced event duration; this effect was opposite to what seen during linopirdine application under similar experimental conditions. Overall, our findings suggest that K IR rather than K M plays a major regulatory role in controlling CCh-induced epileptiform synchronization.

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“…The dramatic consequences of the loss of cholinergic neurons that innervate the hippocampus and the cerebral cortex associated with Alzheimer's disease are evidence of the importance of these neurons for normal behavior (Bierer et al, 1995). Impairment of the cholinergic system has also been reported in other pathologies, for example, in certain forms of epilepsy and in schizophrenia (Holt et al, 1999;Friedman et al, 2007).…”

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confidence: 99%

Silencing of choline acetyltransferase expression by lentivirus‐mediated RNA interference in cultured cells and in the adult rodent brain

Santamaria

Khalfallah

Sauty

et al. 2008

J of Neuroscience Research

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RNA interference (RNAi) is a potent mechanism for local silencing of gene expression and can be used to study loss-of-function phenotypes in mammalian cells. We used RNAi to knockdown specifically the expression of choline acetyltransferase (ChAT), the enzyme of acetylcholine biosynthesis, both in cultured cells and in the adult brain. We first identified a 19-nucleotide sequence in the coding region of rat and mouse ChAT transcripts that constitutes a target for potent silencing of ChAT expression by RNAi. We generated a lentiviral vector that produces both a small hairpin RNA (shRNA) targeting ChAT mRNAs and the enhanced green fluorescent protein (EGFP) reporter protein to facilitate identification of transduced cells. In the cholinergic cell line NG108-15, there was at least 90% less of the ChAT protein, as measured by assaying its enzymatic activity, 3 days postinfection with this vector than in cells infected with a control vector. The vector was used to transduce cholinergic neurons in vivo and reduced ChAT expression strongly and specifically in the cholinergic neurons of the medial septum in adult rats, without affecting the expression of the vesicular acetylcholine transporter. This lentiviral vector is thus a powerful tool for specific inactivation of cholinergic neurotransmission and can therefore be used to study the role of cholinergic nuclei in the brain. This lentiviral-mediated RNAi approach will also allow the development of new animal models of diseases in which cholinergic neurotransmission is specifically altered.

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Cholinergic Dysfunction in Temporal Lobe Epilepsy

Cited by 77 publications

References 51 publications

Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons

Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons

Involvement of inward rectifier and M-type currents in carbachol-induced epileptiform synchronization

Silencing of choline acetyltransferase expression by lentivirus‐mediated RNA interference in cultured cells and in the adult rodent brain

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