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The Journal of Neuroscience, September 1, 2002, 22(17):7502-7508

Immunohistochemical Evidence of Seizure-Induced Activation of trkB Receptors in the Mossy Fiber Pathway of Adult Mouse Hippocampus

Xiao-Ping He¹, Liliana Minichiello⁴, Rüdiger Klein⁵, and James O. McNamara^{1, 2, 3}

Departments of ¹ Medicine (Neurology), ² Neurobiology, and ³ Pharmacology and Molecular Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, ⁴ European Molecular Biology Laboratory, 00016 Monterotondo, Italy, and ⁵ Max-Planck-Institute of Neurobiology, D-82152 Martinsried, Germany

Genetic and pharmacological perturbations suggest that tyrosine receptor kinase B (trkB) receptor activation promotes limbic epileptogenesis, but whether or where trkB activation occurs during epileptogenesis is uncertain. Because activation of trk receptors involves phosphorylation of specific tyrosine residues (Segal et al., 1996), the availability of antibodies that selectively recognize the phosphorylated form of trk receptors at the Shc site permits an immunohistochemical assessment of trk receptor activation. We reported previously increased phospho-specific trk (p-trk) immunoreactivity in the mossy fiber pathway of the hippocampus during epileptogenesis in rats (Binder et al., 1999b). Because the p-trk antibody does not distinguish among trkA, trkB, and trkC, the identity of the neurotrophin receptor(s) undergoing phosphorylation was uncertain. The development of mice carrying a point mutation of the Shc binding site (Y515F) in the trkB gene (trkB^shc) provided an opportunity to test the hypothesis that trkB is the neurotrophin receptor undergoing phosphorylation. Epileptogenesis in wild-type (WT) mice was associated with increased p-trk immunoreactivity in both the mossy fiber pathway and CA3 stratum oriens of hippocampus. In contrast, the epileptogenesis-associated increase of p-trk immunoreactivity was reduced in trkB^shc mutant mice. The development of epileptogenesis as measured by electrophysiological and behavioral indices did not differ between trkB^shc mutant and WT mice. These data demonstrate that the neurotrophin receptor trkB undergoes phosphorylation in the mossy fiber pathway and CA3 stratum oriens of the hippocampus during limbic epileptogenesis. In addition, the signaling pathways activated by the Shc site of trkB exert no detectable regulatory effects on limbic epileptogenesis.

Key words: epileptogenesis; kindling; seizures; neurotrophin; trkB receptor; Shc; hippocampus; phosphorylation

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22177502-07$05.00/0

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