Abstracts

The hallmark pathology of human temporal lobe epilepsy is hippocampal sclerosis, a condition characterized by extensive neuronal loss and glial scaring. Tyrosine kinase B (TrkB), and its ligand BDNF, are potent survival factors for hippocampal neurons [italic]in vitro[/italic]. Whether TrkB regulates the development of hippocampal sclerosis, however, has not been established. To address this question, conditional TrkB null mice were treated with pilocarpine, a drug that produces status epilepticus-induced hippocampal sclerosis. In TrkB null mice, the first coding exon of the TrkB gene is flanked by lox P sites and TrkB expression is eliminated from neurons expressing synapsin 1 promoter-driven Cre recombinase. TrkB expression in these animals is eliminated from the majority of dentate granule and CA3 pyramidal cells, and a subset of cortical, thalamic and amygdala neurons. To induce hippocampal sclerosis, 4 TrkB null and 6 wildtype littermates were treated with 340mg/kg pilocarpine, allowed to seize for 3 hours, and killed 48 hours later. Cell death was assessed by Nissl staining and Fluorojade B staining, the latter labeling dead and dying neurons. Pilocarpine-treatment produced status epilepticus in both wildtype and TrkB null mice. Surprisingly, despite qualitatively similar seizures, dentate hilar cell loss was profoundly [italic]reduced[/italic] in TrkB nulls relative to wildtype mice (wildtype, 52[plusmn]11 Fluorojade B positive neurons/hemisection; null, 8[plusmn]6; P[lt]0.01). Even more surprising, neurons in other regions, including cortex, amygdala and thalamus, were not protected in TrkB nulls (e.g., cingulate cortex; wildtype, 43[plusmn]21; null, 91[plusmn]29). Nissl staining of adjacent sections confirmed the presence of healthy hilar neurons in wildtype control, TrkB null control and TrkB null pilocarpine-treated animals. Consistent with the Fluorojade B findings, significant cell loss in the hilus was only observed in pilocarpine-treated wildtype mice with Nissl staining. Dentate hilar neurons are extremely sensitive to seizure-induced cell death, and the preservation of these neurons in the context of extensive cell death in other regions of the brain is striking. Studies are underway to determine whether this finding reflects reduced invasion of seizure activity into the hippocampus, or whether hippocampal seizure activity is equivalent in these animals and neuroprotection is due to a reduction in toxic effects of TrkB activation. In summary, the present findings indicate that TrkB, either directly or indirectly, may exacerbate hippocampal sclerosis. (Supported by NIH grants NS07370, NS32334 and NINDS grant NS17771. The Epilepsy Foundation and the Ruth K. Broad Foundation.)