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The Journal of Neuroscience, September 9, 2009, 29(36):11294-11303; doi:10.1523/JNEUROSCI.0560-09.2009

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Development/Plasticity/Repair
Brain-Derived Neurotrophic Factor Controls Activity-Dependent Maturation of CA1 Synapses by Downregulating Tonic Activationof Presynaptic Kainate Receptors

Marko Sallert,^1,2 Tomi Rantamäki,¹ Aino Vesikansa,^1,2 Heidi Anthoni,¹ Kirsi Harju,³ Jari Yli-Kauhaluoma,³ Tomi Taira,^1,2 Eero Castren,¹ and Sari E. Lauri^1,2

¹Neuroscience Center, ²Division of Physiology, Department of Biological and Environmental Sciences, and ³Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland

Correspondence should be addressed to Sari Lauri, Neuroscience Center and Department of Bio- and Environmental Sciences/Physiology, P.O. Box 65 (Viikinkaari 1), University of Helsinki, FI-00014 Helsinki, Finland. Email: sari.lauri{at}helsinki.fi

Immature hippocampal synapses express presynaptic kainate receptors (KARs), which tonically inhibit glutamate release. Presynaptic maturation involves activity-dependent downregulation of the tonic KAR activity and consequent increase in release probability; however, the molecular mechanisms underlying this developmental process are unknown. Here, we have investigated whether brain derived neurotrophic factor (BDNF), a secreted protein implicated in developmental plasticity in several areas of the brain, controls presynaptic maturation by regulating KARs.

Application of BDNF in neonate hippocampal slices resulted in increase in synaptic transmission that fully occluded the immature-type KAR activity in area CA1. Conversely, genetic ablation of BDNF was associated with delayed synaptic maturation and persistent presynaptic KAR activity, suggesting a role for endogenous BDNF in the developmental regulation of KAR function. In addition, our data suggests a critical role for BDNF TrkB signaling in fast activity-dependent regulation of KARs. Selective acute inhibition of TrkB receptors using a chemical–genetic approach prevented rapid change in synapse dynamics and loss of tonic KAR activity that is typically seen in response to induction of LTP at immature synapses.

Together, these data show that BDNF–TrkB-dependent maturation of glutamatergic synapses is tightly associated with a loss of endogenous KAR activity. The coordinated action of these two receptor mechanisms has immediate physiological relevance in controlling presynaptic efficacy and transmission dynamics at CA3–CA1 synapses at a stage of development when functional contact already exists but transmission is weak.

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Received Feb. 3, 2009; revised June 23, 2009; accepted June 25, 2009.

Correspondence should be addressed to Sari Lauri, Neuroscience Center and Department of Bio- and Environmental Sciences/Physiology, P.O. Box 65 (Viikinkaari 1), University of Helsinki, FI-00014 Helsinki, Finland. Email: sari.lauri{at}helsinki.fi

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