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.
ABSTRACT
Awake rat brain positron emission tomography (PET) has previously been developed to avoid the influence of anesthesia on the rat brain response. In the present work, we further the awake rat brain scanning methodology to establish simultaneous scanning of two interacting rats in a high resolution, large field of view PET scanner. Awake rat imaging methodology based on point source tracking was adapted to be used in a dedicated human brain scanner, the ECAT high resolution research tomograph (HRRT). Rats could freely run on a horizontal platform of 19.4 × 23â¯cm placed inside the HRRT. The developed methodology was validated using a motion resolution phantom experiment, 3 awake single rat [18F]FDG scans as well as an [18F]FDG scan of 2 interacting rats. The precision of the point source based motion tracking was 0.359â¯mm (standard deviation). Minor loss of spatial resolution was observed in the motion corrected reconstructions (MC) of the resolution phantom compared to the motion-free reconstructions (MF). The full-width-at-half-maximum of the phantom rods were increased by on average 0.37â¯mm in the MC compared to the MF. During the awake scans, extensive motion was observed with rats moving throughout the platform area. The average rat head motion speed was 1.69â¯cm/s. Brain regions such as hippocampus, cortex and cerebellum could be recovered in the motion corrected reconstructions. Relative regional brain uptake of MC and MF was strongly correlated (Pearson's r ranging from 0.82 to 0.95, pâ¯<â¯0.0001). Awake rat brain PET imaging of interacting rats was successfully implemented on the HRRT scanner. The present method allows a large range of motion throughout a large field of view as well as to image two rats simultaneously opening the way to novel rat brain PET study designs.
