The NMDA Receptor Is Coupled to the ERK Pathway by a Direct Interaction between NR2B and RasGRF1

130

134

Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for up-regulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1͞2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors.proteases ͉ excitotoxicity ͉ alcoholism

Section: Results Tpa Is Up-regulated By Ethanol and Ewmentioning

confidence: 78%

Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors

Pawlak

Melchor²,

Matys³

et al. 2005

130

134

“…A role for ERK1͞2 signaling pathway has been proposed in NMDARmediated neuronal death (25). We investigated whether tau neurotoxic effect could be mediated by these kinases.…”

Section: Resultsmentioning

confidence: 99%

NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation

Amadoro

Ciotti

Costanzi

et al. 2006

225

156

The altered function and͞or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer's disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N-methyl-D-aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer's disease and tauopathies where NMDARmediated toxicity is postulated to play a pivotal role. extracellular-regulated kinase ͉ mitogen-activated protein kinase ͉ neurodegenerative diseases ͉ glutamate receptors ͉ Alzheimer's disease

“…Moreover, at the synaptic level, developmental regulation in the signaling pathways utilized by synaptic plasticity mechanisms has been reported in hippocampal and thalamocortical pathways (37)(38)(39). Thus, different NMDA receptor subunits could be linked to distinct intracellular signaling cascades (40,41).…”

Section: Discussionmentioning

confidence: 99%

Dissociation of experience-dependent and -independent changes in excitatory synaptic transmission during development of barrel cortex

Mierau

Meredith

Upton

et al. 2004

A fundamental problem in the study of cortical development is the extent to which the formation and refinement of synaptic circuitry depends upon sensory experience. The barrel cortex is a useful model system to study experience-dependent cortical development because there is a simple mapping of individual whiskers to the corresponding barrel columns in the cortex. We investigated experience-dependent and -independent changes in glutamatergic synaptic transmission in the barrel cortex during the second postnatal week by comparing synaptic responses from whisker-intact mice at postnatal day (P) 7 and P14 with those from whiskerdeprived mice at P14. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA)-receptor-mediated excitatory synaptic responses were recorded from layer 2͞3 pyramidal cells in vitro during voltage-clamp in response to stimulation in layer 4. We observed that the ratio of synaptic AMPA-to NMDA-receptor-mediated current (A͞N ratio) increased with developmental age. The development of the A͞N ratio was unchanged by deprivation of the whisker input throughout the second postnatal week. In contrast, the NMDA-receptor current decay and sensitivity to the NMDA receptor 2B subunitselective antagonist ifenprodil was affected strongly by such deprivation. These results demonstrate a concurrent dissociation between sensory experience-dependent and -independent changes of glutamatergic transmission in the barrel cortex during the second postnatal week. Furthermore, they suggest that the development of subunit composition of synaptic receptors is dependent on sensory experience, whereas maturation of the synaptic A͞N ratio is independent of such experience. Thus, different components of synaptic development may be governed by different developmental rules. S ensory cortical maps are dynamic representations whose developmental refinement depends on sensory experience (1, 2). Extensive plasticity of these cortical maps is seen during early postnatal development, but the capacity for remapping extends into adulthood in primary sensory cortices (3-5).The barrel cortex is a useful model system for studying synaptic mechanisms underlying experience-dependent map plasticity because the topographical organization of the whiskers is preserved in the receptive fields of layer 4 cells enabling selective manipulation of sensory experience. Layer 4 neurons in a cortical column (which define one ''barrel'') receive input primarily from a single whisker on the animal's snout. These cortical barrels develop between postnatal day (P) 0 and P5 (6). Previous studies have demonstrated a critical developmental time period for synaptic plasticity at the thalamocortical input pathway to the barrels, with long-term potentiation induction being possible only during the first postnatal week (7). However, the formation and refinement of succeeding cortical circuitry ensues after this early postnatal stage. Layer 4 spiny neurons in barrels send the majority of their axonal projections to basal den...