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-HT 1A 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-[ 18 F]fluoro-D-glucose ( 18 F-FDG), a radiolabeled analog of glucose, and 2′-methoxyphenyl-( N -2′-pyridinyl)- p - 18 F-fluoro-benzamidoethylpiperazine ( 18 F-MPPF), a radiolabeled 5-HT 1A receptor ligand, to evaluate brain metabolism and 5-HT 1A receptor functionality. Since the 5-HT 1A 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 vitro 18 F-MPPF autoradiography was performed to evaluate changes in 5HT 1A receptor expression. 18 F-FDG PET showed reduction of glucose uptake in cortical structures, whereas 18 F-MPPF PET revealed an enhancement of tracer binding potential (BP ND ) in key areas rich in 5-HT 1A receptor involved in epilepsy, including septum, hippocampus and entorhinal cortex of kindled animals compared to controls. However, in vitro 5-HT 1A receptor autoradiography showed no changes in densitometric signal in any brain region, suggesting that the augmentation in BP ND 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-HT 1A receptor as a valuable epileptogenesis biomarker candidate and a potential therapeutic target.