Neuroscience
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Ampa receptors mediate the majority of excitatory synaptic transmission in the brain. Thus, the mechanisms that control the developmental and activity-dependent changes in the functional synaptic expression of AMPA receptors are of fundamental importance. Here we focus on the role of GluR2 subunit in synaptic function and plasticity.
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Activity dependent modification of receptors in the post-synaptic density is a key determinant in regulating the strength of synaptic transmission during development and plasticity. A major mechanism for this recruitment and removal of postsynaptic proteins is the lateral diffusion in the plane of the plasma membrane. ⋯ In recent years significant progress has been achieved using optical approaches such as single particle tracking (SPT) and fluorescence recovery after photobleach (FRAP). Here, we provide an overview of the principles and methodology of these techniques and highlight the contributions they have made to current understanding of protein mobility in the plasma membrane.
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It has been suggested that NR2B-containing N-methyl-d-aspartate (NMDA) receptors have a selective tendency to promote pro-death signaling and synaptic depression, compared with the survival promoting, synapse potentiating properties of NR2A-containing NMDA receptors. A preferential localization of NR2A-containing NMDA receptors at the synapse in maturing neurons could thus explain differences in synaptic vs. extrasynaptic NMDA receptor signaling. We have investigated whether NMDA receptors can mediate signaling to survival, death, and synaptic potentiation, in dissociated rat neuronal cultures at a developmental stage prior to significant NR2A expression and subunit-specific differences between synaptic and extrasynaptic NMDA receptors. ⋯ Using a cell culture model of synaptic NMDA receptor-dependent synaptic potentiation, we find that this is mediated exclusively by NR2B-containing N-methyl-D-aspartate receptors, as implicated by NR2B-specific antagonists and the use of selective vs. non-selective doses of the NR2A-preferring antagonist NVP-AAM077. Therefore, within a single neuron, NR2B-NMDA receptors are able to mediate both survival and death signaling, as well as model of NMDA receptor-dependent synaptic potentiation. In this instance, subunit differences cannot account for the dichotomous nature of NMDA receptor signaling.
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The stimulation of extrasynaptic N-methyl-D-aspartate (NMDA) receptors triggers cell death pathways and has been suggested to play a key role in cell degeneration and neuron loss associated with glutamate-induced excitotoxicity. In contrast, synaptic NMDA receptors promote neuronal survival. One mechanism through which extrasynaptic NMDA receptors damage neurons may involve Clca1, which encodes a putative calcium-activated chloride channel. ⋯ Microelectrode array recordings revealed that oxygen-glucose deprivation enhances hippocampal network firing rates, which induces c-fos transcription through a signaling pathway that, in contrast to Clca1, is activated by synaptic but not extrasynaptic NMDA receptors. Thus, conditions of low oxygen/glucose lead to the activation of both extrasynaptic and synaptic NMDA receptors that regulate distinct target genes. Clca1 may be part of the genomic death program triggered by extrasynaptic NMDA receptors; it could be a marker for ischemic brain damage and a possible target for therapeutic interventions.