Hypoxia-ischemia modifies postsynaptic GluN2B-containing NMDA receptor complexes in the neonatal mouse brain

Abstract

The N-methyl-D-aspartate-type glutamate receptor (NMDAR)-associated multiprotein complexes are indispensable for synaptic plasticity and cognitive functions. While purification and proteomic analyses of these signaling complexes have been performed in adult rodent and human brain, much less is known about the protein composition of NMDAR complexes in the developing brain and their modifications by neonatal hypoxicischemic (HI) brain injury. In this study, the postsynaptic density proteins were prepared from postnatal day 9 naïve, sham-operated and HI-injured mouse cortex. The GluN2B-containing NMDAR complexes were purified by immunoprecipitation with a mouse GluN2B antibody and subjected to mass spectrometry analysis for determination of the GluN2B binding partners. A total of 71 proteins of different functional categories were identified from the naïve animals as native GluN2B-interacting partners in the developing mouse brain. Neonatal HI reshaped the postsynaptic GluN2B interactome by recruiting new proteins, including multiple kinases, into the complexes; and modifying the existing associations within 1 h of reperfusion. The early responses of postsynaptic NMDAR complexes and their related signaling networks may contribute to molecular processes leading to cell survival or death, brain damage and/or neurological disorders in term infants with neonatal encephalopathy.

DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease

“…ExNMDAR hyperactivity plays a critical role in early synaptic dysfunction and phenotype onset in HD, making it an ideal highly-upstream target for neuroprotection (Milnerwood et al, 2010(Milnerwood et al, , 2012Dau et al, 2014). GluN2B forms a key component of the NMDAR signaling hub, interacting with over 70 cytosolic and membrane proteins to influence neuronal activity and function (Lu et al, 2018). Furthermore, the subunit is subjected to post-translational processes which may be exploited to modify its function (Lussier et al, 2015).…”

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

“…Furthermore, the overexpression of Fyn enhances the phosphorylation of GluN2B in neonatal HIE ( Jiang et al, 2008 ) and exaggerates the neuronal damage, suggesting the pro-death role of SFK in GluN2B-mediated neuronal death. It has also been reported that in early stage of HIE, the phosphorylation of DAPK1 and the P85 subunit of PI3K ( Lu et al, 2018 ) increases. These kinases are known to phosphorylate GluN2B and amplify its downstream pro-death signals ( Takagi et al, 2003 ; Tu et al, 2010 ).…”

“…In neonatal neurons, the GluN2B/SAP102 complex is dominant, while the GluN2A/PSD95 complex gradually increases during development ( van Zundert et al, 2004 ). In the early stage after HIE, the interaction between GluN2B and MAGUK decreases ( Shao et al, 2017 ; Lu et al, 2018 ), while PSD95 subsequently increases its binding with GluN2B ( Shao et al, 2017 ).…”

“…The existing studies indicated that GluN2B might have both pro-death and protective roles in HIE. Although the activation of the pro-death signaling network coupled to GluN2B is activated early after HIE ( Jiang et al, 2008 ; Knox et al, 2014 ; Lu et al, 2018 ), it has been proven that the GluN2B-containing NMDA receptors may also promote neurogenesis in the subventricular zone ( Lai et al, 2016 ). Compared to GluN2B, the role of GluN2A is even more unclear.…”

Systems genetics analysis of the LXS recombinant inbred mouse strains:Genetic and molecular insights into acute ethanol tolerance

“…Nav1 (neuron navigator 1) is restricted to the nervous system and appears to be involved in neuronal migration during early stages of development [ 84 ]. It has been found to be associated with NMDA receptor complexes, a system well known to be influenced by ethanol [ 85 ]. This raises the interesting possibility that Nav1 is shaping the developing brain in a way that ultimately leads to differential ethanol-mediated behavioral responses in the adult, although the fact that it was expressed in the adult brain suggests that it may be participating in other functions.…”