Synaptic modification by L-theanine, a natural constituent in green tea, rescues the impairment of hippocampal long-term potentiation and memory in AD mice

Neuropharmacology. 2018 Aug:138:331-340. doi: 10.1016/j.neuropharm.2018.06.030. Epub 2018 Jun 23.


Synaptic refinement improves synaptic efficiency, which provides a possibility to improve memory in Alzheimer's disease (AD). In the current study, we aimed to investigate the role of L-theanine, a natural constituent in green tea, in hippocampal synaptic transmission and to assess its potential to improve memory in transgenic AD mice. Initially, we found that L-theanine bath application facilitated hippocampal synaptic transmission and reduced paired-pulse facilitation (PPF). These effects were blocked by antagonists of N-methyl-D-aspartic acid receptors and the dopamine D1/5 receptor, and a selective protein kinase A (PKA) inhibitor. Moreover, L-theanine enhanced PKA phosphorylation via dopamine D1/5 receptor activation. L-theanine did not influence hippocampal long-term potentiation (LTP) in the slices obtained from wild-type mice, but rescued the impairment of hippocampal LTP in AD mice. Importantly, systemic application of L-theanine also improved memory and hippocampal LTP in AD mice. Our results demonstrate that L-theanine administration promotes hippocampal dopamine and noradrenaline release, and stimulates PKA phosphorylation. Moreover, the rescued hippocampal LTP in AD mice could be impaired by a PKA inhibitor. Our data reveal that L-theanine ameliorates the impairment of memory and hippocampal LTP in AD mice, likely through dopamine D1/5 receptor-PKA pathway activation. These data warrant the consideration of L-theanine as a candidate for the treatment of AD.

Keywords: Alzheimer's disease; L-theanine; PKA; Synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / psychology
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Glutamates / pharmacology*
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • Male
  • Memory / drug effects
  • Memory / physiology
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / pathology
  • Memory Disorders / physiopathology
  • Mice, Transgenic
  • Neurotransmitter Agents / pharmacology
  • Nootropic Agents / pharmacology*
  • Norepinephrine / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / physiology
  • Tea
  • Tissue Culture Techniques


  • Glutamates
  • Neurotransmitter Agents
  • Nootropic Agents
  • Receptors, Dopamine
  • Receptors, N-Methyl-D-Aspartate
  • Tea
  • theanine
  • Cyclic AMP-Dependent Protein Kinases
  • Dopamine
  • Norepinephrine