Inhibition of glutamine synthetase in the central nucleus of the amygdala induces anhedonic behavior and recurrent seizures in a rat model of mesial temporal lobe epilepsy.
The prevalence of depression and suicide is increased in patients with mesial temporal lobe epilepsy (MTLE); however, the underlying mechanism remains unknown. Anhedonia, a core symptom of depression that is predictive of suicide, is common in patients with MTLE. Glutamine synthetase, an astrocytic enzyme that metabolizes glutamate and ammonia to glutamine, is reduced in the amygdala in patients with epilepsy and depression and in suicide victims. Here, we sought to develop a novel model of anhedonia in MTLE by testing the hypothesis that deficiency in glutamine synthetase in the central nucleus of the amygdala (CeA) leads to epilepsy and comorbid anhedonia. Nineteen male Sprague-Dawley rats were implanted with an osmotic pump infusing either the glutamine synthetase inhibitor methionine sulfoximine [MSO (n=12)] or phosphate buffered saline [PBS (n=7)] into the right CeA. Seizure activity was monitored by video-intracranial electroencephalogram (EEG) recordings for 21days after the onset of MSO infusion. Sucrose preference, a measure of anhedonia, was assessed after 21days. Methionine sulfoximine-infused rats exhibited recurrent seizures during the monitoring period and showed decreased sucrose preference over days when compared with PBS-infused rats (p<0.01). Water consumption did not differ between the PBS-treated group and the MSO-treated group. Neurons were lost in the CeA, but not the medial amygdala, lateral amygdala, basolateral amygdala, or the hilus of the dentate gyrus, in the MSO-treated rats. The results suggest that decreased glutamine synthetase activity in the CeA is a possible common cause of anhedonia and seizures in TLE. We propose that the MSO CeA model can be used for mechanistic studies that will lead to the development and testing of novel drugs to prevent seizures, depression, and suicide in patients with TLE.
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Shaun E
SE
Gruenbaum
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Helen
H
Wang
Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA.
Hitten P
HP
Zaveri
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Amber B
AB
Tang
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
Tih-Shih W
TS
Lee
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Tore
T
Eid
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: roni.dhaher@yale.edu.
Roni
R
Dhaher
D000679:Amygdala / Q000201:enzymology*; D000704:Analysis of Variance; D059445:Anhedonia / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D066274:Central Amygdaloid Nucleus / Q000201:enzymology*; D015897:Comorbidity; D003866:Depressive Disorder / Q000201:enzymology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000172:deficiency*; D006624:Hippocampus / Q000502:physiology; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000201:enzymology
D004791:Enzyme Inhibitors; D008717:Methionine Sulfoximine; D005974:Glutamate-Ammonia Ligase
Anhedonia; Central amygdala; Epilepsy; Glutamine synthetase; Sucrose preference