Impairment of conditioned freezing to tone, but not to context, in Fyn-transgenic mice: relationship to NMDA receptor subunit 2B function

Eur J Neurosci. 2005 Mar;21(5):1359-69. doi: 10.1111/j.1460-9568.2005.03955.x.

Abstract

We previously demonstrated that transgenic mice overexpressing Fyn tyrosine kinase exhibit higher seizure susceptibility and enhanced tyrosine phosphorylation of several proteins, including the N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B). In the present study, we analysed behavioural phenotypes, especially conditioned fear responses, of Fyn-transgenic (TG) mice to better understand the role of Fyn in learned emotional behaviour. Tone-dependent conditioned freezing was significantly attenuated in Fyn-TG mice, whereas context-dependent freezing was unaffected. Neither massed nor spaced conditioning ameliorated the attenuation of tone-dependent freezing. However, the selective NR2B antagonist ifenprodil, when administered before conditioning, restored tone-dependent freezing in Fyn-TG mice at a dose that did not affect freezing in wild-type (WT) mice. These results suggest that impairment of tone-dependent conditioned freezing in Fyn-TG mice is caused by disruption of the NR2B-containing NMDA receptor function. Tyrosine phosphorylation of brain proteins, including NR2B, was enhanced in Fyn-TG mice compared with that in WT mice. We also found that ifenprodil significantly suppressed the enhanced tyrosine phosphorylation. Thus, our data support the notion that NMDA receptor activity is tightly correlated with protein tyrosine phosphorylation, and Fyn might be one key molecule that controls tone-dependent conditioned freezing through the regulation of NMDA receptor function.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation / methods
  • Amygdala / drug effects
  • Amygdala / physiology
  • Animals
  • Behavior, Animal
  • Blotting, Western / methods
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology*
  • Electroshock / adverse effects
  • Evoked Potentials / drug effects
  • Evoked Potentials / radiation effects
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fear*
  • Freezing Reaction, Cataleptic / drug effects
  • Freezing Reaction, Cataleptic / physiology
  • Freezing Reaction, Cataleptic / radiation effects*
  • Immunohistochemistry / methods
  • Injections, Intraventricular / methods
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Piperidines / pharmacology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-fyn
  • Reaction Time / drug effects
  • Reaction Time / radiation effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Synaptosomes / radiation effects
  • Time Factors
  • Tyrosine / metabolism
  • src-Family Kinases / genetics
  • src-Family Kinases / physiology*

Substances

  • Excitatory Amino Acid Antagonists
  • NR2B NMDA receptor
  • Piperidines
  • Proto-Oncogene Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Tyrosine
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn
  • src-Family Kinases
  • ifenprodil