Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism

Neuropsychopharmacology. 2015 Aug;40(9):2269-77. doi: 10.1038/npp.2015.76. Epub 2015 Mar 18.

Abstract

Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF(Met/Met)) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF(Met/Met) mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF(Met/Met) mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics*
  • Central Amygdaloid Nucleus / cytology*
  • Conditioning, Classical / physiology
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Extinction, Psychological / drug effects
  • Fear / physiology
  • Glutamic Acid / metabolism*
  • In Vitro Techniques
  • Male
  • Methionine / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • N-Methylaspartate / pharmacology
  • Neurons / drug effects
  • Neurons / physiology*
  • Piperidines / pharmacology
  • Polymorphism, Single Nucleotide / genetics*
  • Synapses / genetics*
  • Valine / genetics

Substances

  • Brain-Derived Neurotrophic Factor
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Piperidines
  • Glutamic Acid
  • N-Methylaspartate
  • Methionine
  • Valine
  • ifenprodil