Abstract
Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
Highlights
Acetylcholine (ACh) exerts a wide range of neuromodulatory effects in numerous physiological and pathological states [1]
The cholinergic agonist pilocarpine induces status epilepticus in vivo and recently it was shown that administration of pilocarpine causes a 6-fold increase of hippocampal ACh release paralleling the development of tonic seizures [12,13,14]
While hippocampal slices are known to produce epileptiform bursting under nonsynaptic conditions such as low-Ca2+ milieu [19,20,21], we hypothesized that different, synaptic mechanisms account for epileptiform discharges synchronization in synaptic blockers aCSF, unlike nonsynaptic mechanisms of low-Ca2+ seizure-like activity (SLA) (Fig 1B)
Summary
Acetylcholine (ACh) exerts a wide range of neuromodulatory effects in numerous physiological and pathological states [1]. The cholinergic agonist pilocarpine induces status epilepticus in vivo and recently it was shown that administration of pilocarpine causes a 6-fold increase of hippocampal ACh release paralleling the development of tonic seizures [12,13,14]. High doses of nicotine induce seizures in animals, and mutations in genes coding for nAChR subunit are associated with seizures in humans [15,16,17]. Despite these multiple links to epilepsy, the exact function of cholinergic receptors in patterning of hippocampal synchronization remains unclear
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