Upsetting the Balance VGF and the Regulation of Body Weight

through homologous recombination show deficits in These results leave several questions open. Does the spatial learning and a decrease in the protein synthesis– LTD-inducing protocol stimulate CREB phosphorylation dependent late phase of hippocampal LTP (but show on Ser-133 and does it activate CREB-mediated gene normal early-phase LTP). In hippocampal neurons, CREB transcription? Is such phosphorylation directly medi-phosphorylation depends on complicated and inter-ated by CaMKIV or does this kinase act through other acting kinase cascades, involving an ERK/MAP kinase signaling pathways? Is CREB activation required for late cascade, PKA (Impey et al., 1998), and CaMKIV (Diesser-LTD that is induced by synaptic stimulation in cerebellar oth et al., 1998). slices? Do mice deficient in CREB exhibit deficits in So far, examples of CREB-mediated synaptic plastic-cerebellar-dependent motor learning? Finally, is CREB ity all involve the long-term enhancement of synaptic also required for hippocampal late LTD? And if so, how transmission (i.e., LTP and long-term facilitation). How-can activation of a single transcription factor contribute ever, synapses also display long-term decreases in syn-to both synaptic potentiation and depression? Clearly, aptic transmission, such as long-term depression (LTD) CREB's new role as a regulator of synaptic depression (see Linden and Connor, 1995). Up until now, it had not provides a powerful potentiating stimulus for future been known whether CREB-regulated gene expression studies. is also necessary for these inhibitory forms of synaptic plasticity. And if gene activation by CREB is required Steven A. Siegelbaum for long-term decreases in synaptic strength, what are Center for Neurobiology and Behavior the upstream signaling cascades that are needed for its Department of Pharmacology recruitment? In this issue of Neuron, Ahn, Ginty, and Howard Hughes Medical Institute Linden (1999) address these questions for the late, pro-Columbia University tein synthesis–dependent phase of LTD in cultured cere-New York, New York 10032 bellar Purkinje neurons. sis–independent component and a late, protein synthe-sis–dependent component (Linden, 1996). Now, the Lin-den group has gone on to show that late LTD in Purkinje neurons requires CREB activation and that this activation requires CaMKIV. a powerful molecular scalpel, Ahn et al. (1999) find that expression of a dominant-negative form of CREB (which of Body Weight inhibits CREB binding to DNA and gene activation) blocks late, but not early, LTD. Dominant-negative forms of CaMKII and CaMKIV, as well as a calmodulin trap Animal survival depends upon the ability to maintain a that is targeted to the nucleus, also inhibit late, but not …