Reduced Metabotropic Glutamate Receptor Type 5 Availability in the Epileptogenic Hippocampus: An in vitro Study
Maria Zimmermann1,2, Luciano Minuzzi2,3, Arturo Aliaga Aliaga2,4
1Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada.
Abstract:
Abnormalities in the expression of metabotropic glutamate receptor type 5 (mGluR5) have been observed in the hippocampus of patients with drug-resistant mesial Temporal Lobe Epilepsy (mTLE). Ex-vivo studies in mTLE hippocampal surgical specimens have shown increased mGluR5 immunoreactivity, while in vivo whole brain imaging using positron emission tomography (PET) demonstrated reduced hippocampal mGluR5 availability. To further understand mGluR5 abnormalities in mTLE, we performed a saturation autoradiography study with [3H]ABP688 (a negative mGluR5 allosteric modulator). We aimed to evaluate receptor density (Bmax) and dissociation constants (KD) in hippocampal mTLE surgical specimens and in non-epilepsy hippocampi from necropsy controls. mTLE specimens showed a 43.4% reduction in receptor density compared to control hippocampi, which was independent of age, sex and KD (multiple linear regression analysis). There was no significant difference in KD between the groups, which suggests that the decreased mGluR5 availability found in vivo with PET cannot be attributed to reduced affinity between ligand and binding site. The present study supports that changes within the epileptogenic tissue include mGluR5 internalization or conformational changes that reduce [3H]ABP688 binding, as previously suggested in mTLE patients studied in vivo.
Insights
Metabotropic glutamate receptor type 5 (mGluR5) density is significantly reduced in the hippocampus of epilepsy patients. This finding in mesial Temporal Lobe Epilepsy (mTLE) suggests receptor internalization, not altered binding affinity.
Area of Science:
- Neuroscience
- Epileptology
- Pharmacology
Background:
- Metabotropic glutamate receptor type 5 (mGluR5) expression abnormalities are linked to drug-resistant mesial Temporal Lobe Epilepsy (mTLE).
- Conflicting findings exist: increased mGluR5 immunoreactivity in ex-vivo mTLE tissue versus reduced hippocampal availability in vivo via PET imaging.
Purpose of the Study:
- To investigate mGluR5 receptor density (Bmax) and binding affinity (KD) in hippocampal surgical specimens from mTLE patients compared to controls.
- To clarify the discrepancy between ex-vivo and in vivo mGluR5 findings in mTLE.
Main Methods:
- Saturation autoradiography using [3H]ABP688, a negative mGluR5 allosteric modulator.
- Analysis of hippocampal surgical specimens from mTLE patients and necropsy controls.
- Multiple linear regression analysis to assess the impact of age, sex, and KD on receptor density.
Main Results:
- mTLE specimens exhibited a 43.4% reduction in mGluR5 receptor density (Bmax) compared to controls.
- This reduction was independent of age, sex, and dissociation constant (KD).
- No significant difference in KD was observed between mTLE and control groups.
Conclusions:
- The reduced hippocampal mGluR5 availability in mTLE patients, observed in vivo, is likely due to receptor internalization or conformational changes within the epileptogenic tissue.
- These changes affect ligand binding rather than altering the receptor's intrinsic affinity for the ligand.
