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The Journal of Neuroscience, August 18, 2004, 24(33):7215-7224; doi:10.1523/JNEUROSCI.2045-04.2004

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Development/Plasticity/Repair
Brain-Derived Neurotrophic Factor Induces Hyperexcitable Reentrant Circuits in the Dentate Gyrus

Ryuta Koyama,¹ Maki K. Yamada,¹ Shigeyoshi Fujisawa,¹ Ritsuko Katoh-Semba,² Norio Matsuki,¹ and Yuji Ikegaya¹

¹Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan, and ²Institute for Developmental Research, Aichi Human Service Center, Aichi 480-0392, Japan

Aberrant sprouting and synaptic reorganization of the mossy fiber (MF) axons are commonly found in the hippocampus of temporal lobe epilepsy patients and result in the formation of excitatory feedback loops in the dentate gyrus, a putative cellular basis for recurrent epileptic seizures. Using ex vivo hippocampal cultures, we show that prolonged hyperactivity induces MF sprouting and the resultant network reorganizations and that brain-derived neurotrophic factor (BDNF) is necessary and sufficient to evoke these pathogenic plasticities. Hyperexcitation induced an upregulation of BDNF protein expression in the MF pathway, an effect mediated by L-type Ca²⁺ channels. The neurotrophin receptor tyrosine kinase (Trk)B inhibitor K252a or function-blocking anti-BDNF antibody prevented hyperactivity-induced MF sprouting. Even under blockade of neural activity, local application of BDNF to the hilus, but not other subregions, was capable of initiating MF axonal remodeling, eventually leading to dentate hyperexcitability. Transfecting granule cells with dominant-negative TrkB prevented axonal branching. Thus, excessive activation of L-type Ca²⁺ channels causes granule cells to express BDNF, and extracellularly released BDNF stimulates TrkB receptors present on the hilar segment of the MFs to induce axonal branching, which may establish hyperexcitable dentate circuits.

Key words: hippocampus; granule cell; mossy fiber; epilepsy; sprouting; BDNF

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Received Jan 15, 2004; revised June 25, 2004; accepted June 28, 2004.

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