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

被引:13
作者
Gruenbaum, Shaun E. [1 ]
Wang, Helen [1 ]
Zaveri, Hitten P. [2 ]
Tang, Amber B. [1 ]
Lee, Tih-Shih W. [3 ]
Eid, Tore [1 ]
Dhaher, Roni [1 ]
机构
[1] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
Anhedonia; Epilepsy; Glutamine synthetase; Central amygdala; Sucrose preference; STATUS EPILEPTICUS; ANTIEPILEPTIC DRUGS; DEPRESSIVE BEHAVIOR; SUICIDAL IDEATION; GLUCOCORTICOID-RECEPTOR; ETHANOL-CONSUMPTION; PILOCARPINE MODEL; BRAIN; EXPRESSION; ACID;
D O I
10.1016/j.yebeh.2015.07.015
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
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 21 days after the onset of MSO infusion. Sucrose preference, a measure of anhedonia, was assessed after 21 days. 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. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:96 / 103
页数:8
相关论文
共 65 条
  • [11] Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression
    Choudary, PV
    Molnar, M
    Evans, SJ
    Tomita, H
    Li, JZ
    Vawter, MP
    Myers, RM
    Bunney, WE
    Akil, H
    Watson, SJ
    Jones, EG
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (43) : 15653 - 15658
  • [12] 5-Aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy
    Dhaher, Roni
    Damisah, Eyiyemisi C.
    Wang, Helen
    Gruenbaum, Shaun E.
    Ong, Caroline
    Zaveri, Hitten P.
    Gruenbaum, Benjamin F.
    Eid, Tore
    [J]. NEUROBIOLOGY OF DISEASE, 2014, 67 : 18 - 23
  • [13] Lesions of the extended amygdala in C57BL/6J mice do not block the intermittent ethanol vapor-induced increase in ethanol consumption
    Dhaher, Ronnie
    Finn, Deborah
    Snelling, Christopher
    Hitzemann, Robert
    [J]. ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH, 2008, 32 (02) : 197 - 208
  • [14] Behavioral changes resulting from the administration of cycloheximide in the pilocarpine model of epilepsy
    dos Santos, JG
    Longo, BM
    Blanco, MM
    de Oliveira, MGM
    Mello, LEN
    [J]. BRAIN RESEARCH, 2005, 1066 (1-2) : 37 - 48
  • [15] Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats
    Eid, Tore
    Ghosh, Arko
    Wang, Yue
    Beckstrom, Henning
    Zaveri, Hitten P.
    Lee, Tih-Shih W.
    Lai, James C. K.
    Malthankar-Phatak, Gauri H.
    de Lanerolle, Nihal C.
    [J]. BRAIN, 2008, 131 : 2061 - 2070
  • [16] Epileptogenicity of cortical dysplasia in temporal lobe dual pathology: an electrophysiological study with invasive recordings
    Fauser, S
    Schulze-Bonhage, A
    [J]. BRAIN, 2006, 129 : 82 - 95
  • [17] Behavioral alterations in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainate
    Groeticke, Ina
    Hoffmann, Katrin
    Loescher, Wolfgang
    [J]. EXPERIMENTAL NEUROLOGY, 2008, 213 (01) : 71 - 83
  • [18] Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice
    Groeticke, Ina
    Hoffmann, Katrin
    Loescher, Wolfgang
    [J]. EXPERIMENTAL NEUROLOGY, 2007, 207 (02) : 329 - 349
  • [19] Expression of gluatamine synthetase and glutamate dehydrogenase in the latent phase and chronic phase in the kainate model of temporal lobe epilepsy
    Hammer, Janniche
    Alvestad, Silje
    Osen, Kirsten K.
    Skare, Oivind
    Sonnewald, Ursula
    Ottersen, Ole Petter
    [J]. GLIA, 2008, 56 (08) : 856 - 868
  • [20] Synaptic plasticity in glutamatergic and GABAergic neurotransmission following chronic memantine treatment in an in vitro model of limbic epileptogenesis
    He, Shuijin
    Bausch, Suzanne B.
    [J]. NEUROPHARMACOLOGY, 2014, 77 : 379 - 386