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Published on: May 16, 2019
Medial perforant path inhibition mediated by mGluR7 is reduced after status epilepticus
Kristopher J Bough1, David D Mott, Raymond J Dingledine
1School of Medicine, Dept. of Pharmacology, Emory University, Rollins Research Center, Rm. 5002, 1510 Clifton Road, Atlanta, GA 30322-3090, USA. kbough@emory.edu
Abstract:
Metabotropic glutamate receptor (mGluR)-mediated inhibition within the dentate gyrus is altered after epilepsy. Whether these changes occur during the developmental period of the disease (i.e., the latent period) has not yet been investigated. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the lateral (LPP) and medial perforant path (MPP) simultaneously in adult mouse hippocampal slices 3-9 days after pilocarpine (PILO)-induced status epilepticus. Genetically manipulated mice (mGluR8 knockout and mGluR4/8 double knockout) and pharmacologically selective agonists were used to identify specific mGluR subtypes affected after PILO. Pharmacological activation of mGluR7 by L-AP4 in both wild-type and mGluR4/8 double knockout mice selectively reduced fEPSPs in the MPP, but not LPP, and this level of inhibition was significantly reduced 3-9 days after PILO-induced SE. Activation of mGluR2/3 reversibly depressed the fEPSP slopes in both the MPP and LPP, but no alterations were noted after PILO. mGluR8 activation selectively inhibited evoked responses in the LPP, but not in the MPP, and this level of inhibition did not change after PILO treatment. These data suggest that reduced presynaptic inhibition mediated by mGluR7, but not mGluR2/3 or mGluR8, may play a role during the latent period in generating hyperexcitability in the dentate and thereby contribute to epileptogenesis.
Insights
Reduced metabotropic glutamate receptor 7 (mGluR7) inhibition in the dentate gyrus during epilepsy's latent phase may promote hyperexcitability. This suggests mGluR7 dysfunction contributes to epileptogenesis.
Area of Science:
- Neuroscience
- Epilepsy Research
- Molecular Biology
Background:
- Metabotropic glutamate receptor (mGluR)-mediated inhibition in the dentate gyrus is crucial for regulating neuronal excitability.
- Epilepsy is associated with alterations in mGluR function, but changes during the latent period remain unexplored.
Purpose of the Study:
- To investigate alterations in mGluR-mediated inhibition in the dentate gyrus during the latent period of epilepsy.
- To identify specific mGluR subtypes involved in these changes following status epilepticus.
Main Methods:
- Field excitatory postsynaptic potentials (fEPSPs) were recorded in adult mouse hippocampal slices after pilocarpine-induced status epilepticus (SE).
- Genetically modified mice (mGluR8 knockout and mGluR4/8 double knockout) and selective mGluR agonists were utilized.
- Electrophysiological recordings assessed the effects of mGluR7, mGluR2/3, and mGluR8 activation on synaptic transmission.
Main Results:
- Activation of mGluR7 selectively reduced fEPSPs in the medial perforant path (MPP), an effect significantly diminished 3-9 days after SE.
- mGluR2/3 activation reversibly depressed fEPSPs in both MPP and lateral perforant path (LPP), with no observed alterations post-SE.
- mGluR8 activation inhibited responses in the LPP, and this effect remained unchanged after SE.
Conclusions:
- Reduced presynaptic inhibition mediated by mGluR7 occurs during the latent period of epilepsy.
- This mGluR7 dysfunction may contribute to dentate gyrus hyperexcitability and epileptogenesis.
- mGluR2/3 and mGluR8 do not appear to play a significant role in the latent phase alterations investigated.
