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MEDICINE 2013;2:274 -283

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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.

While randomized controlled trials demonstrated 94-95% efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike messenger RNA (mRNA) vaccines [1,2], efficacy in immunocompromised patients has not been established. We aimed to understand serologic response to mRNA vaccination in patients with chronic lymphocytic leukemia (CLL), a population of interest given the immunocompromised state associated with this malignancy and disease-directed therapies, as well as incomplete immune responses following other vaccinations [3][4][5][6][7][8][9][10]. MethodsWe examined 44 consecutive patients with CLL who received two doses of mRNA vaccine (BNT162b2 or mRNA-1273) between 1/2/21 and 3/12/21 and were tested for anti-SARS-CoV-2 S1/S2 antibodies. Serology testing was performed in routine clinical practice with the Liaison® SARS-CoV-2 S1/S2 IgG assay (DiaSorin; Saluggia, Italy) with ≥15 AU/mL constituting a positive result. Baseline demographics, treatment history and laboratory parameters prior to first dose of COVID-19 vaccine were collected. Logistic regression was used to examine relationship between baseline characteristics and positive serology testing; all other statistics are descriptive. Analyses were performed using Stata 16 [11]. This retrospective study was institutional review board approved.