Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKII␣ promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.Studies have demonstrated a pivotal role for transcription in learning and memory, from early experiments showing that RNA synthesis inhibitors block long-term memory without altering short-term memory, to studies in Drosophila, Aplysia, and mice demonstrating that transcription factor cAMP response element binding protein (CREB) is involved in long-term memory (Lonze and Ginty 2002;Kaplan and Abel 2003). Use-dependent changes in synaptic strength in the hippocampus and other brain regions are thought to underlie memory storage. One intensely studied form of synaptic plasticity is hippocampal long-term potentiation (LTP), a persistent, activity-dependent form of synaptic enhancement (Bliss and Richter-Levin 1993;Martin and Morris 2002). CREB has been shown to be involved in certain types of hippocampal LTP as well as long-term memory (for review, see Kaplan and Abel 2003). In most cases, CREB activates transcription of target genes by recruiting the coactivator CREB-binding protein (CBP) (Goodman and Smolik 2000), via the interaction between the Ser-133 phosphorylated kinase-inducible domain (KID) of CREB and the KIX domain of CBP (Chrivia et al. 1993). CBP stimulates transcription in two ways: via its intrinsic histone acetyltransferase (HAT) activity and via recruitment of components of the general transcriptional machinery (for review, see Vo and Goodman 2001).A role for CBP in memory storage was first demonstrated in a mouse model of Rubinstein-Taybi Syndrome (Oike et al. 1999). RTS is a human developmental disorder characterized by retarded growth and reduced mental function (Rubinstein and Taybi 1963;Hennekam et al. 1992;Cantani and Gagliesi 1998), caused by breakpoints, microdeletions and point mutations in CBP (Petrij et al. 1995;Coupry et al. 2004). Mice heterozygous for an inhibitory truncated CBP allele, lacking the HAT domain and carboxyl terminus, showed many features of RTS such as growth retardation, cardiac anomalies, and skel...

alpha-Internexin is a 66 kDa protein that copurifies with intermediate filaments (IF) from rat spinal cord and optic nerve. This protein is axonally transported in rat optic nerve along with the neurofilament triplet proteins in slow component a. Polymerization in vitro and distribution in vivo confirm that alpha-internexin is a neuronal IF. We raised 2 highly specific monoclonal antibodies to alpha-internexin which were applied to frozen rat brain sections and Western blots of cytoskeletal extracts. These results indicate that alpha-internexin is primarily an axonal protein found in most, if not all, neurons of the CNS. Immunoreactive proteins of similar molecular weight were found in cytoskeletal extracts of CNS tissue from several additional species, including mouse and cow. While the distribution of alpha-internexin as given by immunocytochemical methods is similar to that of low molecular weight neurofilament protein (NF-L) in the adult, its distribution in the embryo is far more extensive. At embryonic day 16, when the expression of NF-L is still limited to a relatively small number of cells and levels of expression are low, alpha-internexin is already found at much higher levels and in cells not yet expressing NF-L in detectable quantities. Similar results are found at embryonic day 12. These data suggest that neuronal IF in the developing nervous system contain a higher proportion of alpha-internexin than their adult counterparts, and that expression of alpha-internexin precedes that of NF-L in many or most neurons of the developing brain.

Ligands from the B7 family bind to receptors of the CD28 family, which regulate early T cell activation in lymphoid organs and control inflammation and autoimmunity in peripheral tissues. PD-1, a member of the CD28 family, is an inhibitory receptor on T cells and is responsible for their dysfunction in infectious diseases and cancers. The complex mechanisms controlling expression and signaling of PD-1 and PD-L1 are emerging. Recently completed and ongoing clinical trials that target these molecules have shown remarkable success by generating durable clinical responses in some cancer patients. In chronic viral infections, preclinical data reveal that targeting PD-1 and its ligands can improve T cell responses and viral clearance. There is also promise in stimulating this pathway for the treatment of autoimmune and inflammatory disorders.

While neurofilaments have long been considered early markers of neuronal differentiation, they cannot be detected in most newly postmitotic neurons of the developing central nervous system (CNS). Here we show that these neurons already express the neuronal intermediate filament protein alpha-internexin at high levels. alpha-internexin is expressed by most, if not all, neurons as they begin differentiation and shows no overlap with vimentin, whose expression in the CNS is restricted to mitotic neuronal precursors. In the adult, alpha-internexin is the only intermediate filament gene expressed by the cerebellar granule cells, the source of the thin-caliber parallel fibers; conversely, neurofilament proteins are highly expressed in large neurons, which express alpha-internexin at low levels. These data suggest that neuronal intermediate filaments may regulate axonal stability and/or diameter through changes not only in their number, but also in their subunit composition.