Rapamycin Suppresses Mossy Fiber Sprouting But Not Seizure Frequency in a Mouse Model of Temporal Lobe Epilepsy

被引:196
作者
Buckmaster, Paul S. [1 ,2 ]
Lew, Felicia H. [1 ,3 ]
机构
[1] Stanford Univ, Dept Comparat Med, Stanford, CA 94305 USA
[2] Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA
[3] Washington State Univ, Coll Vet Med, Pullman, WA 99164 USA
关键词
SPONTANEOUS RECURRENT SEIZURES; ECTOPIC GRANULE CELLS; INDUCED STATUS EPILEPTICUS; RAT DENTATE GYRUS; C-FOS EXPRESSION; SYNAPTIC REORGANIZATION; MAMMALIAN TARGET; FASCIA-DENTATA; TUBEROUS SCLEROSIS; PILOCARPINE MODEL;
D O I
10.1523/JNEUROSCI.4852-10.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Temporal lobe epilepsy is prevalent and can be difficult to treat effectively. Granule cell axon (mossy fiber) sprouting is a common neuropathological finding in patients with mesial temporal lobe epilepsy, but its role in epileptogenesis is unclear and controversial. Focally infused or systemic rapamycin inhibits the mammalian target of rapamycin (mTOR) signaling pathway and suppresses mossy fiber sprouting in rats. We tested whether long-term systemic treatment with rapamycin, beginning 1 d after pilocarpine-induced status epilepticus in mice, would suppress mossy fiber sprouting and affect the development of spontaneous seizures. Mice that had experienced status epilepticus and were treated for 2 months with rapamycin displayed significantly less mossy fiber sprouting (42% of vehicle-treated animals), and the effect was dose dependent. However, behavioral and video/EEG monitoring revealed that rapamycin- and vehicle-treated mice displayed spontaneous seizures at similar frequencies. These findings suggest mossy fiber sprouting is neither pro-nor anti-convulsant; however, there are caveats. Rapamycin treatment also reduced epilepsy-related hypertrophy of the dentate gyrus but did not significantly affect granule cell proliferation, hilar neuron loss, or generation of ectopic granule cells. These findings are consistent with the hypotheses that hilar neuron loss and ectopic granule cells might contribute to temporal lobe epileptogenesis.
引用
收藏
页码:2337 / 2347
页数:11
相关论文
共 116 条
[1]   SYNAPTIC REORGANIZATION BY MOSSY FIBERS IN HUMAN EPILEPTIC FASCIA-DENTATA [J].
BABB, TL ;
KUPFER, WR ;
PRETORIUS, JK ;
CRANDALL, PH ;
LEVESQUE, MF .
NEUROSCIENCE, 1991, 42 (02) :351-363
[2]  
BABB TL, 1989, J NEUROSCI, V9, P2562
[3]   Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease [J].
Backman, SA ;
Stambolic, V ;
Suzuki, A ;
Haight, J ;
Elia, A ;
Pretorius, J ;
Tsao, MS ;
Shannon, P ;
Bolon, B ;
Ivy, GO ;
Mak, TW .
NATURE GENETICS, 2001, 29 (04) :396-403
[4]   Contributions of mossy fiber and CA1 pyramidal cell sprouting to dentate granule cell hyperexcitability in kainic acid-treated hippocampal slice cultures [J].
Bausch, SB ;
McNamara, JO .
JOURNAL OF NEUROPHYSIOLOGY, 2004, 92 (06) :3582-3595
[5]   Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures [J].
Bengzon, J ;
Kokaia, Z ;
Elmer, E ;
Nanobashvili, A ;
Kokaia, M ;
Lindvall, O .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10432-10437
[6]   Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: Electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy [J].
Bouilleret, V ;
Ridoux, V ;
Depaulis, A ;
Marescaux, C ;
Nehlig, A ;
La Salle, GL .
NEUROSCIENCE, 1999, 89 (03) :717-729
[7]   Design logic of a cannabinoid receptor signaling network that triggers neurite outgrowth [J].
Bromberg, Kenneth D. ;
Ma'ayan, Avi ;
Neves, Susana R. ;
Iyengar, Ravi .
SCIENCE, 2008, 320 (5878) :903-909
[8]   Inhibition of the Mammalian Target of Rapamycin Signaling Pathway Suppresses Dentate Granule Cell Axon Sprouting in a Rodent Model of Temporal Lobe Epilepsy [J].
Buckmaster, Paul S. ;
Ingram, Elizabeth A. ;
Wen, Xiling .
JOURNAL OF NEUROSCIENCE, 2009, 29 (25) :8259-8269
[9]  
Buckmaster PS, 1997, J COMP NEUROL, V385, P385
[10]  
Buckmaster PS, 2002, J NEUROSCI, V22, P6650