Severity of pilocarpine-induced seizures affected by acetylcholine receptors

Severity of pilocarpine-induced seizures affected by acetylcholine receptors

Researchers from the University of Montana and Stanford University have shown that the muscarinic excitation of parvalbumin-positive (PV) interneurons is partially responsible for the severity of pilocarpine-induced seizures (PISs).

Activation of muscarinic acetylcholine receptors (mAChRs) is widely acknowledged as a mechanism for the generation of seizures. These seizures can be induced by the acetylcholine agonist pilocarpine, a method commonly used for rodent models of epilepsy in research.

It has previously been shown that M1 mAChRs (M1Rs) are crucial for the generation of pilocarpine-induced seizures in mice, but it was not known how their activation disrupts excitation/inhibition imbalance.

PV interneurons are a major form of GABAergic neurons responsible for modulating neuronal excitability throughout the central nervous system.
In addition, activation of M1Rs is known to strongly depolarise hippocampal CA1 PV cells, but it was not clear whether activation of these mAChRs on PV cells contributed to the generation of PISs in vivo.

In this study, the team led by Professor J Josh Lawrence, showed:

  • Action potential (AP) frequency in PV cells increased significantly after the bath application of pilocarpine to hippocampal slices.
  • Pilocarpine directly increases activity in PV cells independent of glutamatergic excitation.
  • In a subset of PV cells, pilocarpine-induced depolarisation led to depolarisation block (DB) – a cessation in neuronal firing.
  • In PV-M1KO mice, there was no significant increase in AP firing after pilocarpine application. This also prevents PV cells from entering DB.
  • Behavioural studies showed reduced seizure severity in PV-M1KO mice compared to WT, 30-45 minutes after injection of pilocarpine.

Pilocarpine is only a partial agonist for M1R activation and has a reduced effect compared with the endogenous neurotransmitter, acetylcholine (ACh). This study shows that a pathologic rise in ACh would inhibit GABA release from PV interneurons, reducing inhibition in the PV circuit and contributing to seizures. This suggests a therapeutic target for presynaptic inhibition and a reduction in cholinergic over-excitation of PV cells to moderate the severity of seizures.

Pilocarpine is also known to activate other mAChRs. These receptors could also play a role in generating and sustaining PISs, contributing to the initiation of a seizure and its seriousness.

In order to carry out the electrophysiological experiments the group used a Scientifica Patch Pro 2000 system. This system is ideal for users who prefer a large fixed stage platform for mounting a variety of manipulators and other devices close to the sample chamber.

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Paper Reference:

Yi F., DeCan E., Stoll K., Marceau E., Deisseroth K., Lawrence J.J. (2014) Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures Epilepsia, [Epub ahead of print] doi: 10.1111/epi.12883

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