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 neur otrophic factor (GDNF) and neurturin (NRTN), and their receptor components, the transmembrane c-Ret tyrosine kinase and the glycosylphosphatidylinosit ol-anchored GDNF family receptor (GFR) alpha1 and alpha2 in limbic structur es. We demonstrate here that epileptogenesis, as assessed in the hippocampa l-kindling model, is markedly suppressed in mice lacking GFR alpha2. Moreov er, at 6 to 8 wk after having reached the epileptic state, the hyperexcitab ility is lower in GFR alpha2 knock-out mice as compared with wild-type mice . These results provide evidence that signaling through GFR alpha2 is invol ved in mechanisms regulating the development and persistence of kindling ep ilepsy. Our data suggest that GDNF and NRTN may modulate seizure susceptibi lity by altering the function of hilar neuropeptide Y-containing interneuro ns and entorhinal cortical afferents at dentate granule cell synapses.