Higher Seizure Susceptibility and Enhanced Tyrosine Phosphorylation of N-Methyl-d-Aspartate Receptor Subunit 2B in fyn Transgenic Mice

Abstract

Earlier work has suggested that Fyn tyrosine kinase plays an important role in synaptic plasticity. To understand the downstream targets of Fyn signaling cascade in neurons, we generated transgenic mice expressing either a constitutively activated form of Fyn or native Fyn in neurons of the forebrain. Transgenic mice expressing mutant Fyn exhibited higher seizure activity and were prone to sudden death. Mice overexpressing native Fyn did not show such an obvious epileptic phenotype, but they exhibited accelerated kindling in response to once-daily stimulation of the amygdala. Tyrosine phosphorylation of at least three proteins was enhanced in the forebrains of both native and mutant fyn transgenic mice; tyrosine phosphorylation of these three proteins was reduced infyn knockout mice, suggesting that they are substrates of Fyn. One of these proteins was identified as the subunit 2B (NR2B) of theN-methyl-d-aspartate (NMDA) receptor. Administration of MK-801, a noncompetitive NMDA receptor antagonist, retarded kindling in mice overexpressing native Fyn, as well as wild-type mice, suggests that the accelerated kindling in mice overexpressing Fyn is also mediated by the NMDA receptor activity. Our results thus suggest that tyrosine phosphorylation by Fyn might be involved in regulation of the susceptibility of kindling, one form of the NMDA receptor-mediated neuronal plasticity.