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The Journal of Neuroscience, October 12, 2005, 25(41):9535-9543; doi:10.1523/JNEUROSCI.2191-05.2005

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Cellular/Molecular
Neuronal Depolarization Controls Brain-Derived Neurotrophic Factor-Induced Upregulation of NR2C NMDA Receptor via Calcineurin Signaling

Kazunori Suzuki, Masaaki Sato, Yosuke Morishima, and Shigetada Nakanishi

Department of Molecular and Systems Biology, Graduate School of Biostudies, and Department of Biological Sciences, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan

In the developing cerebellum, switching of subunit composition of NMDA receptors occurs in granule cells from NR2B subunit-containing receptors to NR2C subunit-containing receptors. This switching of subunit composition plays an important role in the establishment of functional mossy fiber- granule cell synaptic transmission in the mature cerebellar network. The mechanism underlying NR2C upregulation in developing granule cells, however, has to date remained to be determined. In granule cells cultured in low (5 mM) KCl, brain-derived neurotrophic factor (BDNF) upregulated NR2C mRNA via the TrkB-extracellular signal-regulated kinase (ERK) 1/2 cascade and promoted the formation of an NR2C-containing NMDA receptor complex. In granule cells cultured in high (25 mM) KCl, depolarization stimulated voltage-sensitive Ca²⁺ channels. The resultant increase in intracellular Ca²⁺ activated Ca²⁺/calmodulin-dependent calcineurin phosphatase and blocked NR2C mRNA upregulation. Interestingly, the depolarization-induced Ca²⁺ increase simultaneously upregulated BDNF mRNA via Ca²⁺/calmodulin-dependent protein kinase (CaMK). Consequently, when calcineurin was inhibited by its inhibitor FK506 under the depolarizing condition, the CaMK-mediated increase in BDNF became a stimulatory signal, and the endogenous BDNF autocrine system was capable of upregulating NR2C mRNA via the common TrkB-ERK cascade. The importance of the BDNF-TrkB pathway was further supported by a significant reduction in NR2C in normally migrated granule cells of TrkB^-/- knock-out mice in vivo. The convergent mechanism of the BDNF and Ca²⁺ signaling cascades thus plays an important regulatory role in NR2C induction in granule cells during cerebellar development.

Key words: gene regulation; NMDA receptor; BDNF; cerebellar granule cell; calcineurin; ERK

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Received May 31, 2005; revised August 31, 2005; accepted September 1, 2005.

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