Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling

Addict Biol. 2017 Nov;22(6):1706-1718. doi: 10.1111/adb.12433. Epub 2016 Jul 25.


Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor-independent form of LTP (CAF LTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB-mediated signaling required for the expression of CAF LTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAF LTP, a process that requires cytosolic free Ca2+ . Consistent with the involvement of IRS2 signals in caffeine-mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2-/- mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3-kinase (PI3K) pathway. These findings indicate that TrkB-IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

Keywords: NMDA-independent synaptic plasticity; PI3K-AKT pathway; TrkB receptor; hippocampus; insulin receptors.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / drug effects
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Caffeine / pharmacology*
  • Central Nervous System Stimulants / pharmacology*
  • Female
  • Insulin Receptor Substrate Proteins / drug effects
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism*
  • Male
  • Mice
  • Models, Animal
  • Neuronal Plasticity / drug effects*
  • Signal Transduction / drug effects*


  • Brain-Derived Neurotrophic Factor
  • Central Nervous System Stimulants
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Caffeine