Brain-derived neurotrophic factor controls activity-dependent maturation of CA1 synapses by downregulating tonic activation of presynaptic kainate receptors.
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.
Sallert
Marko
M
Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland.
Rantamäki
Tomi
T
Vesikansa
Aino
A
Anthoni
Heidi
H
Harju
Kirsi
K
Yli-Kauhaluoma
Jari
J
Taira
Tomi
T
Castren
Eero
E
Lauri
Sari E
SE
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020813:Receptor, trkB / Q000235:genetics; D018092:Kainic Acid Receptors / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D020813:Receptor, trkB; D018092:Kainic Acid Receptors; D017661:Receptors, Presynaptic