JAK/STAT signaling is among the most rapid means by which cells can send signals from the plasma membrane to the nucleus. Nicolas et al. (2012) show that STAT3, an isoform particularly abundant at synapses, is the critical downstream target in NMDAR-LTD. So, by its location deeper than the previously known induction mechanisms, the JAK/STAT pathway may get us closer to the central mystery of NMDAR-LTD: the

maintenance ABT-263 order mechanism that keeps its synaptic depression going. Yet here, too, lies an enigma. STATs are transcription factors. But Nicolas et al. (2012) show that the persistence of LTD does not need transcription. Indeed, NMDAR-LTD does not need a nucleus at all, because NMDAR-LTD can be induced and maintained for at least 3 hr in synapses in a surgically isolated CA1 radiatum, from which the pyramidal cell bodies

have been removed. Moreover, selleck inhibitor inhibitors of STAT3 dimerization, a key step in its activation that leads to its translocation to the nucleus, prevent NMDAR-LTD, but an inhibitor of STAT3 binding to DNA does not. What roles does STAT3 play other than as a transcription factor? Very few have been described, despite the voluminous work on the JAK/STAT pathway in immunology and cancer. One line of research, however, suggests that STAT3 regulates tubulin dynamics by binding to stathmin, which interacts with tubulin (Gao and Bromberg, 2006). This suggests a role in intracellular trafficking. As mentioned, STAT3 phosphorylation by JAK in the cytosol of nonneural cells leads to STAT3 dimerization that then translocates to the nucleus. Although its function in NMDAR-LTD does not require DNA binding, Nicolas and colleagues show that STAT3 nonetheless translocates to the nucleus of neurons when synapses are stimulated in NMDAR-LTD. Perhaps it is not the arrival at the nucleus, but the transport away from the synapse, that reflects too the importance of STAT3 in NMDAR-LTD. In nonneural cells, STAT3 transcriptional signaling by activated receptors is initiated by receptor-mediated endocytosis and trafficking of the transcription factor in

endosomes through the cytosol to the perinuclear region (Bild et al., 2002). Perhaps in neurons, this pathway, triggered by STAT dimerization, is also used to transport both STAT and other proteins, including AMPARs, away from the synapse. Whether the JAK2/STAT3 pathway is close to the maintenance mechanism of NMDAR-LTD or not, the agents that Nicolas et al. (2012) use, many of them developed to suppress the growth of cancer cells driven by persistent JAK2/STAT3 signaling (Levy and Darnell, 2002), can now be used as specific agents to test the role of NMDAR-LTD in behavior. Indeed, there are already indications in Alzheimer’s disease mouse models that JAK plays a role in spatial working memory (Chiba et al., 2009)—intriguingly, one of the types of memory not mediated by PKMζ (Sacktor, 2011).