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Actions of MPTP and MPP+ on synaptic transmission in guinea-pig hippocampal slices
Abstract:
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes a Parkinson's disease-like syndrome in man, monkeys, and mice. We studied the effects of MPTP and its metabolite, MPP+, on neuronal properties and synaptic transmission in isolated slices of guinea-pig hippocampus using intra- and extracellular recording methods. Addition of MPTP to the superfusate (50 to 100 microM) produced the following effects: Excitatory postsynaptic potentials and extracellularly recorded population spikes, evoked by stimulation of the Schaffer collaterals were increased in amplitude during the application period (30 min). Within 30 min of washing in normal solution, synaptic transmission was blocked, although axonal population action potentials could still be elicited. The block of synaptic transmission was prevented by prior incubation in pargyline, an inhibitor of monoamine oxidase. The membrane potential and resistance of single pyramidal neurons were virtually unaffected; action potentials elicited by depolarizing intracellular current pulses were also unchanged. MPP+ (50 microM) blocked synaptic transmission during the application period by a pargyline-in-sensitive mechanism. These results suggest that MPP+ blocks synaptic transmission in the hippocampus at a presynaptic site. This effect may be relevant for the acute action of MPTP and may provide some insight into its chronic action on nigrostriatal neurons.
Insights
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite MPP+ impair synaptic transmission in the hippocampus. MPP+ blocks transmission presynaptically, offering insights into MPTP
Area of Science:
- Neuroscience
- Neuropharmacology
- Cellular Electrophysiology
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a Parkinson's disease-like syndrome.
- Understanding MPTP's mechanism of action is crucial for Parkinson's disease research.
Purpose of the Study:
- To investigate the effects of MPTP and its metabolite MPP+ on hippocampal neuronal properties and synaptic transmission.
- To elucidate the site and mechanism of synaptic blockade induced by MPP+.
Main Methods:
- Electrophysiological recordings (intra- and extracellular) in isolated guinea-pig hippocampal slices.
- Application of MPTP and MPP+ to superfusate.
- Stimulation of Schaffer collaterals to evoke synaptic responses.
- Use of pargyline, a monoamine oxidase inhibitor, to investigate mechanisms.
Main Results:
- MPTP transiently increased excitatory postsynaptic potentials and population spikes.
- MPTP-induced synaptic transmission block was reversible and prevented by pargyline.
- MPP+ induced a rapid, pargyline-insensitive blockade of synaptic transmission.
- Neuronal membrane properties and action potential generation remained largely unaffected.
Conclusions:
- MPP+ likely blocks hippocampal synaptic transmission at a presynaptic site via a pargyline-insensitive mechanism.
- These findings suggest a role for presynaptic mechanisms in MPTP neurotoxicity.
- The study provides insights into both the acute and chronic effects of MPTP on neuronal systems.