Essential role of presynaptic NMDA receptors in activity-dependent BDNF secretion and corticostriatal LTP

Neuron. 2014 Dec 3;84(5):1009-22. doi: 10.1016/j.neuron.2014.10.045. Epub 2014 Nov 20.


Activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) in postsynaptic dendrites is required for long-term potentiation (LTP) of many excitatory synapses, but the role of presynaptic axonal NMDARs in synaptic plasticity remains to be clarified. Here we report that axonal NMDARs play an essential role in LTP induction at mouse corticostriatal synapses by triggering activity-induced presynaptic secretion of brain-derived neurotrophic factor (BDNF). Genetic depletion of either BDNF or the NMDAR subunit GluN1 specifically in cortical axons abolished corticostriatal LTP in response to theta burst stimulation (TBS). Furthermore, functional axonal NMDARs were required for TBS-triggered prolonged axonal Ca(2+) elevation and BDNF secretion, supporting the notion that activation of axonal NMDARs induces BDNF secretion via enhancing Ca(2+) signals in the presynaptic nerve terminals. These results demonstrate that presynaptic NMDARs are equally important as postsynaptic NMDARs in LTP induction of corticostriatal synapses due to their role in mediating activity-induced presynaptic BDNF secretion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Cerebral Cortex / cytology*
  • Corpus Striatum / cytology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics
  • Long-Term Potentiation / physiology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Models, Biological
  • Neurons / drug effects
  • Neurons / physiology*
  • Receptor, trkB / immunology
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synapses / genetics
  • Synapses / physiology*
  • Time Factors
  • Valine / analogs & derivatives
  • Valine / pharmacology


  • Antibodies
  • Brain-Derived Neurotrophic Factor
  • Excitatory Amino Acid Antagonists
  • Luminescent Proteins
  • Receptors, N-Methyl-D-Aspartate
  • 2-amino-5-phosphopentanoic acid
  • Receptor, trkB
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Valine