Reduced Metabotropic Glutamate Receptor Type 5 Availability in the Epileptogenic Hippocampus: An in vitro Study

Maria Zimmermann; Luciano Minuzzi; Arturo Aliaga Aliaga; Marie-Christine Guiot; Jeffery A Hall; Jean-Paul Soucy; Gassan Massarweh; Salah El Mestikawy; Pedro Rosa-Neto; Eliane Kobayashi

doi:10.3389/fneur.2022.888479

Reduced Metabotropic Glutamate Receptor Type 5 Availability in the Epileptogenic Hippocampus: An in vitro Study

Front Neurol. 2022 Jul 22:13:888479. doi: 10.3389/fneur.2022.888479. eCollection 2022.

Authors

Maria Zimmermann^{1

2}, Luciano Minuzzi^{2

3}, Arturo Aliaga Aliaga^{2

4}, Marie-Christine Guiot⁵, Jeffery A Hall¹, Jean-Paul Soucy^{1

4}, Gassan Massarweh⁴, Salah El Mestikawy⁶, Pedro Rosa-Neto^{1

2}, Eliane Kobayashi¹

Affiliations

¹ Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, QC, Canada.
² Translational Neuroimaging Laboratory, Douglas Research Institute, McGill University, Montréal, QC, Canada.
³ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
⁴ PET Unit, McConnell Brain Imaging Centre, Montréal, QC, Canada.
⁵ Department of Pathology, Montréal Neurological Institute, Montréal, QC, Canada.
⁶ Department of Psychiatry, Douglas Research 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 (B_max) and dissociation constants (K_D) 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 K_D (multiple linear regression analysis). There was no significant difference in K_D 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.

Keywords: [3H]ABP688; autoradiography; hippocampus; mGluR5; temporal lobe epilepsy.