PET Neuroimaging Reveals Serotonergic and Metabolic Dysfunctions in the Hippocampal Electrical Kindling Model of Epileptogenesis

Abstract

Glucose metabolism and serotonergic neurotransmission have been reported to play an important role in epileptogenesis. We therefore aimed to use neuroimaging to evaluate potential alterations in serotonin 5-HT1A receptor and glucose metabolism during epileptogenesis in the rat electrical kindling model. To achieve this goal, we performed positron emission tomography (PET) imaging in a rat epileptogenesis model triggered by electrical stimulation of the hippocampus using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG), a radiolabeled analog of glucose, and 2 -methoxyphenyl-(N-2 -pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF), a radiolabeled 5-HT1A receptor ligand, to evaluate brain metabolism and 5-HT1A receptor functionality. Since the 5-HT1A receptor is also highly expressed in astrocytes, glial fibrillary acidic protein (GFAP) immunofluorescence was performed to detect astrogliosis arising from the kindling procedure once the study was finalized. Lastly, in vitro18F-MPPF autoradiography was performed to evaluate changes in 5HT1A receptor expression. 18F-FDG PET showed reduction of glucose uptake in cortical structures, whereas 18F-MPPF PET revealed an enhancement of tracer binding potential (BPND) in key areas rich in 5-HT1A receptor involved in epilepsy, including septum, hippocampus and entorhinal cortex of kindled animals compared to controls. However, in vitro 5-HT1A receptor autoradiography showed no changes in densitometric signal in any brain region, suggesting that the augmentation in BPND found by PET could be caused by reduction of synaptic serotonin. Importantly, astroglial activation was detected in the hippocampus of kindled rats. Overall, electrical kindling induced hypometabolism, astrogliosis and serotonergic alterations in epilepsy-related regions. Furthermore, the present findings point to 5-HT1A receptor as a valuable epileptogenesis biomarker candidate and a potential therapeutic target.