Modifications in the number and complement of glutamatesensing receptors in the post-synaptic membrane are key mechanisms used to adjust synaptic strength. There is abundant evidence that the trafficking of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors is critical for long-term potentiation (LTP) and long-term depression of synaptic strength [see (Malinow and Malenka 2002;Song and Huganir 2002;Bredt and Nicoll 2003) for reviews], and emerging evidence suggests that trafficking of NMDA receptors is also important for synaptic plasticity (Lan et al. 2001;Roche et al. 2001;Nong et al. 2003;Scott et al. 2004;Lavezzari et al. 2004;Washbourne et al. 2004;Barria and Malinow 2002;Rao and Craig 1997;Quinlan et al. 1999;Watt et al. 2000). Although the identification and characterization of protein components involved in the trafficking of glutamate receptors has been an active and productive area of research, there has been little progress in understanding how changes in membrane lipid components affect the function and trafficking of glutamate receptors. Recent experimental evidence suggests that up to 60% of NMDA receptors are located in lipid rafts (Besshoh et al. Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DAG, diacylglycerol; EPSC, excitatory post-synaptic current; IL, interleukin; ISP-1, myriocin; LTP, long-term potentiation; MS, mass spectrometry; nSMase2, neutral sphingomyelinase 2; PBS, phosphate-buffered saline; PKA/C, protein kinase A/C; PLC, phospholipase C; TNF, tumor necrosis factor. AbstractThe insertion and removal of NMDA receptors from the synapse are critical events that modulate synaptic plasticity. While a great deal of progress has been made on understanding the mechanisms that modulate trafficking of NMDA receptors, we do not currently understand the molecular events required for the fusion of receptor containing vesicles with the plasma membrane. Here, we show that sphingomyelin phosphodiesterase 3 (also known as neutral sphingomyelinase-2) is critical for tumor necrosis factor (TNF) a-induced trafficking of NMDA receptors and synaptic plasticity. TNFa initiated a rapid increase in ceramide that was associated with increased surface localization of NMDA receptor NR1 subunits and a specific clustering of NR1 phosphorylated on serines 896 and 897 into lipid rafts. Brief applications of TNFa increased the rate and amplitude of NMDA-evoked calcium bursts and enhanced excitatory post-synaptic currents. Pharmacological inhibition or genetic mutation of neutral sphingomyelinase-2 prevented TNFa-induced generation of ceramide, phosphorylation of NR1 subunits, clustering of NR1, enhancement of NMDA-evoked calcium flux and excitatory post-synaptic currents.

Background-Infection with HIV can result in a debilitating CNS disorder known as HIV dementia (HIV-D). Since the advent of highly active antiretroviral therapy (HAART), the incidence of HIV-D has declined, but the prevalence continues to increase. In this new era of HIV-D, traditional biomarkers such as CSF viral load and monocyte chemotactic protein 1 levels are less likely to be associated with dementia in patients on HAART and biomarkers that can predict HIV-D have not yet been identified.

Background:The role of Kv1.3 in regulating T cell differentiation and memory is incompletely understood. Results: A dominant negative mutation of Kv1.3 mediates reversion of T EM into T CM through SMAD3-dependent cell cycle changes. Conclusion: Signaling through Kv1.3 is a mechanism by which T EM may revert to T CM . Significance: These findings suggest a novel role for Kv1.3 in T cell differentiation and memory responses.