Activity-dependent neurotrophin signaling underlies developmental switch of Ca2+ channel subtypes mediating neurotransmitter release

J Neurosci. 2013 Nov 27;33(48):18755-63. doi: 10.1523/JNEUROSCI.3161-13.2013.


At the nerve terminal, neurotransmitter release is triggered by Ca(2+) influx through voltage-gated Ca(2+) channels (VGCCs). During postnatal development, VGCC subtypes in the nerve terminal switch at many synapses. In immature rodent cerebella, N-type and P/Q-type VGCCs mediate GABAergic neurotransmission from Purkinje cells (PCs) to deep nuclear cells, but as animals mature, neurotransmission becomes entirely P/Q-type dependent. We reproduced this developmental switch in rat cerebellar slice culture to address the underlying mechanism. Chronic block of cerebellar neuronal activity with tetrodotoxin (TTX) in slice culture, or in vivo, reversed the switch, leaving neurotransmission predominantly N-type channel-dependent. Brain-derived neurotrophic factor or neurotrophin-4 rescued this TTX effect, whereas pharmacological blockade of neurotrophin receptors mimicked the TTX effect. In PC somata, unlike in presynaptic terminals, TTX had no effect on the proportion of Ca(2+) channel subtype currents. We conclude that neuronal activity activates the neurotrophin-TrkB signaling pathway, thereby causing the N-to-P/Q channel switch in presynaptic terminals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthetics, Local / pharmacology
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium Channels / drug effects
  • Calcium Channels / physiology*
  • Calcium Channels, N-Type / physiology
  • Calcium Channels, P-Type / physiology
  • Calcium Channels, Q-Type / physiology
  • Cerebellum / drug effects
  • Cerebellum / physiology
  • Electrophysiological Phenomena / physiology
  • Female
  • Genetic Vectors
  • Immunohistochemistry
  • In Vitro Techniques
  • Lentivirus / genetics
  • Male
  • Nerve Endings / drug effects
  • Nerve Endings / metabolism
  • Nerve Endings / physiology
  • Nerve Growth Factors / physiology*
  • Neurotransmitter Agents / metabolism*
  • Presynaptic Terminals / physiology
  • Rats
  • Rats, Wistar
  • Receptor, trkB / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tetrodotoxin / pharmacology


  • Anesthetics, Local
  • Brain-Derived Neurotrophic Factor
  • Calcium Channels
  • Calcium Channels, N-Type
  • Calcium Channels, P-Type
  • Calcium Channels, Q-Type
  • Nerve Growth Factors
  • Neurotransmitter Agents
  • Tetrodotoxin
  • Receptor, trkB