Long-term potentiation increases tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit 2B in rat dentate gyrus in vivo.

Abstract

Long-term potentiation (LTP) is a form of synaptic memory that may subserve developmental and behavioral plasticity. An intensively investigated form of LTP is dependent upon N-methyl-D-aspartate (NMDA) receptors and can be elicited in the dentate gyrus and hippocampal CAI. Induction of this type of LTP is triggered by influx of Ca2+ through activated NMDA receptors, but the downstream mechanisms of induction, and even more so of LTP maintenance, remain controversial. It has been reported that the function of NMDA receptor channel can be regulated by protein tyrosine kinases and protein phosphatases and that inhibition of protein tyrosine kinases impairs induction of LTP. Herein we report that LTP in the dentate gyrus is specifically correlated with tyrosine phosphorylation of the NMDA receptor subunit 2B in an NMDA receptor-dependent manner. The effect is observed with a delay of several minutes after LTP induction and persists in vivo for several hours. The potential relevance of this post-translational modification to mechanisms of LTP and circuit plasticity' is discussed.Long-term potentiation (LTP) is regarded as a form of synaptic memory that may subserve experience-dependent plasticity at the circuit and behavioral level (1). Although the relevance of experimentally induced LTP to normal brain function remains uncertain (2, 3), there is widespread agreement that cellular cascades recruited in LTP play a role in brain development (4, 5) and in learning (6-8). An intensively studied form of LTP is dependent upon N-methyl-D-aspartate (NMDA) receptors and can be elicited in the dentate gyrus and hippocampal CAl. Induction of this type of LTP is triggered by influx of Ca2+ through activated NMDA receptors, but the downstream mechanisms of induction, and even more so of LTP maintenance, are controversial (1, 6). These mechanisms may involve modulation of protein kinases and phosphatases, long implicated in short-and intermediate-term neuronal plasticity (9-11). Major candidates are ubiquitous serine/threonine protein kinases (12). Activation of Ca2+/calmodulin-dependent protein kinase II (CAM kinase II) has been specifically implicated in induction, and CAM kinase II-upregulation of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in induction and possibly in maintenance of NMDA receptor-dependent LTP (6, 13). Protein tyrosine kinase have also been implicated in LTP; thus, it has been reported that inhibitors of tyrosine kinases impair LTP induction in the dentate gyrus and CAl (14,15) We have recently reported that sensory experience results in enhanced tyrosine phosphorylation of a set of synaptic proteins in the insular cortex of the behaving rat (17). One of these proteins, of 180 kDa, is concentrated in the post-synaptic density and displays properties of the NMDA receptor subunit 2B (NR2B) (18,19). This finding led us to test whether an experimentally controlled form of experience-dependent synaptic modification (i.e., LTP) also results in enhanced tyrosine phosphorylation of the...

Phosphorylation–dependent interaction of the N‐methyl‐ d‐aspartate receptor ε2 subunit with phosphatidylinositol 3‐kinase

“…We demonstrated that both the tyrosine phosphorylation of NMDAR«2 and the binding of p85 to NMDAR«2 were decreased in Fyn-de®cient mice. Because the level of tyrosine phosphorylation of NMDAR«2 is increased in LTP and taste learning (Rosenblum et al 1996;Rostas et al 1996;Rosenblum et al 1997), it is possible that the decreases of both tyrosine phosphorylation of NMDAR«2 and amounts of p85 bound to NMDAR«2 in Fyn-de®cient mice could be at least in part responsible for impaired LTP. Interestingly, Src family kinases could increase the activity of NMDARz1-NMDAR«1 channels but not of NMDARz1-NMDAR«2 channels (Kohr & Seeburg 1996).…”

Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

“…LTP-inducing tetanic stimulation increases tyrosine phosphorylation of the GluN2B subunit of the NMDAR in the hippocampus 52,53 . Here we found that TBS caused an increase in GluN2B tyrosine phosphorylation that depended on Src (Fig.…”

Characterization of Fyn-mediated Tyrosine Phosphorylation Sites on GluRε2 (NR2B) Subunit of the N-Methyl-d-aspartate Receptor

“…NMDA receptor-mediated currents are potentiated by Src-family tyrosine kinases and suppressed by tyrosine phosphatases (23,24). In addition, taste-learning increases tyrosine phosphorylation of GluR⑀2 in the rat insular cortex, and tyrosine phosphorylation of GluR⑀2 is increased after induction of LTP in the dentate gyrus of anesthetized adult rats (25)(26)(27). It is reported that Src and Fyn do not potentiate the current through recombinant GluR1-GluR⑀2 channels in 293 cells (28).…”