Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor α2

Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor α2

^*Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, SE-221 85 Lund, Sweden; and ^†Program for Molecular Neurobiology, Institute of Biotechnology, 00014, University of Helsinki, Helsinki, Finland

Communicated by Tomas Hökfelt, Karolinska Institute, Stockholm, Sweden (received for review April 14, 2000)

Abstract

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) α1 and α2 in limbic structures. We demonstrate here that epileptogenesis, as assessed in the hippocampal kindling model, is markedly suppressed in mice lacking GFRα2. Moreover, at 6 to 8 wk after having reached the epileptic state, the hyperexcitability is lower in GFRα2 knock-out mice as compared with wild-type mice. These results provide evidence that signaling through GFRα2 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.

Footnotes

↵ ‡ To whom reprint requests should be addressed. E-mail: Zaal.Kokaia{at}neurol.lu.se.
Abbreviations:

AD,

after discharge;

BDNF,

brain-derived neurotrophic factor;

GDNF,

glial cell line-derived neurotrophic factor;

GFR,

GDNF family receptor;

LPP,

lateral perforant path;

LTP,

long-term potentiation;

MPP,

medial perforant path;

NPY,

neuropeptide Y;

NRTN,

neurturin;

PPD,

paired-pulse depression