Cortical-subcortical dysconnectivity expressed by attenuated cortical c-fos induction by acute amphetamine treatment or acute swim stress in mice with reduced NMDA receptor1 expression

Abstract

Reelin is a large glycoprotein that is secreted into the extracellular matrix. In the embryonic brain, the binding of Reelin to its receptors ApoER2 and VLDLR induces subcellular events that include the activation Fyn tyrosine kinase, and plays a crucial role in cortical formation. Reelin signaling is also involved in postnatal brain functions such as dendrite development and synaptic plasticity. However, the molecular events involved in Reelin signaling in the postnatal brain remain to be elucidated. Here, we evaluated the proteins downstream of Reelin signaling by comparing the tyrosine-phosphorylated proteins in the postnatal hippocampus of heterozygous and homozygous reeler and wild-type mice, by Western blot analyses. We found that the levels of several phosphoproteins were highest in the hippocampus of the heterozygous reeler mice. The most prominent increase was of two 180-kDa phosphoproteins, which were identified as the NR2A and NR2B subunits of NMDA-R. The amounts of these proteins also increased in the hippocampus of heterozygous reeler mice. However, the mRNA levels of the NMDA-R subunits, determined by quantitative RT-PCR, were the same as in wild-type mice. We also found that the increase in NR2A and NR2B proteins in heterozygous reeler was dependent on Fyn, because this change was absent in heterozygous reeler/homozygous Fyn-deficient double-mutant mice. Thus, the NMDA-R protein level is regulated by the Reelin protein level in a Fyn-dependent manner in the mouse brain.