Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor alpha 2.
Seizure activity regulates gene expression for glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), and their receptor components, the transmembrane c-Ret tyrosine kinase and the glycosylphosphatidylinositol-anchored GDNF family receptor (GFR) alpha 1 and alpha 2 in limbic structures. We demonstrate here that epileptogenesis, as assessed in the hippocampal kindling model, is markedly suppressed in mice lacking GFR alpha 2. Moreover, at 6 to 8 wk after having reached the epileptic state, the hyperexcitability is lower in GFR alpha 2 knock-out mice as compared with wild-type mice. These results provide evidence that signaling through GFR alpha 2 is involved in mechanisms regulating the development and persistence of kindling epilepsy. Our data suggest that GDNF and NRTN may modulate seizure susceptibility by altering the function of hilar neuropeptide Y-containing interneurons and entorhinal cortical afferents at dentate granule cell synapses.
Nanobashvili
A
A
Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, SE-221 85 Lund, Sweden.
Airaksinen
M S
MS
Kokaia
M
M
Rossi
J
J
Asztély
F
F
Olofsdotter
K
K
Mohapel
P
P
Saarma
M
M
Lindvall
O
O
Kokaia
Z
Z
D000818:Animals; D029721:Drosophila Proteins; D004827:Epilepsy / Q000235:genetics*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006624:Hippocampus / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007696:Kindling, Neurologic / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*
D029721:Drosophila Proteins; C494988:Gfra1 protein, mouse; C494991:Gfra2 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse