Studies have shown that peripheral levels of corticosterone correlate with the magnitudes of two well-described physiological models of memory, long-term potentiation (LTP) and primed burst (PB) potentiation. In the present experiments, the authors investigated the effects of experimenter-controlled manipulations of the levels of corticosterone on the magnitude of hippocampal PB potentiation in urethane-anesthetized rats. Primed burst potentiation is a long-lasting (at least 30 minutes) increase in the amplitude of the CA1 population spike and EPSP slope in response to physiologically patterned stimulation of the hippocampal commissure. The levels of serum corticosterone were controlled by implanting corticosterone pellets in adrenalectomized rats (ADX/PELLET). In the first experiment, a significant negative linear correlation between elevated (stress) levels of serum corticosterone (greater than 20 micrograms/dL) and the magnitude of PB potentiation in ADX/PELLET subjects (r = 0.60, P < .05) was found. In the second experiment, the shape of the corticosterone-PB potentiation function was different at low and intermediate levels of corticosterone than it was at high levels of corticosterone: There was a positive correlation at low levels (0-10 micrograms/dL), a peak response at intermediate levels (11-20 micrograms/dL), and a negative correlation at high levels (21-93 micrograms/dL) of corticosterone. Thus, the overall relationship between corticosterone and PB potentiation is an inverted-U function. These findings provide strong support for the hypothesis that corticosterone exerts a concentration-dependent biphasic influence on the expression of hippocampal plasticity.

Mutations in ␣-synuclein are known to be associated with Parkinson's disease (PD). The coexistence of this neuronal protein with ubiquitin and proteasome subunits in Lewy bodies in sporadic disease suggests that alterations of ␣-synuclein catabolism may contribute to the pathogenesis of PD. The degradation pathway of ␣-synuclein has not been identified nor has the kinetics of this process been described. We investigated the degradation kinetics of both wild-type and A53T mutant 6XHis-tagged ␣-synuclein in transiently transfected SH-SY5Y cells. Degradation of both isoforms followed firstorder kinetics over 24 h as monitored by the pulse-chase method. However, the t1 ⁄2 of mutant ␣-synuclein was 50% longer than that of the wild-type protein (p < 0.01). The degradation of both recombinant proteins and endogenous ␣-synuclein in these cells was blocked by the selective proteasome inhibitor ␤-lactone (40 M), indicating that both wild-type and A53T mutant ␣-synuclein are degraded by the ubiquitin-proteasome pathway. The slower degradation of mutant ␣-synuclein provides a kinetic basis for its intracellular accumulation, thus favoring its aggregation.

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IntroductionThe ability of neoplastic cells to evade the immune system remains a formidable barrier limiting the success of immunotherapy. Tumor cells can employ various mechanisms to escape detection by immune cells. These can include down-regulation of major histocompatibility complex (MHC) class I expression, 1-4 production of immunosuppressive cytokines such as transforming growth factor-␤, 1,5 up-regulation of Fas ligand, 6 and deregulation of zeta chain on T cells. 7 In both mouse and human, natural killer (NK) cells are composed of different subsets, which are characterized by the expression of inhibitory and/or activating receptors specific for MHC class I determinants. [8][9][10][11] In mice, these receptors belong to the family of Ly49 receptors, which are lectinlike molecules. 12 The human counterpart, killer immunoglobulin-like receptors, belongs to the immunoglobulin superfamily. 11 A small percentage of T cells in mice also express Ly49 receptors. 13 It has been shown that binding of the inhibitory receptors by the appropriate class I molecules results in generation of negative signals leading to inactivation of NK cell functions. [13][14][15] This inhibitory signal has been shown to dominate over activating stimuli. 15 Furthermore, the rapid rejection of tumors lacking the expression of MHC class I by NK cells demonstrates the pivotal role MHC plays in regulating NK function. [16][17][18] In spite of these studies demonstrating the functions of the inhibitory receptors in vitro, the in vivo functions of these receptors on either NK or T cells remain to be elucidated.One potential means for tumor escape may be by expressing MHC class I determinants at a level that allows sufficient binding of the Ly49 inhibitory receptors and thus escape from NKmediated killing. In To examine the effects of blockade of the inhibitory receptors on antitumor activity, we have used a C1498 mouse leukemia model and F(abЈ) 2 fragments of 5E6 monoclonal antibody (mAb), 21 which binds to Ly49C and I receptors, for in vitro as well as in vivo studies. The use of F(abЈ) 2 fragments allowed us to examine the responses that are due to blocking the Ly49 receptors without For personal use only. on May 12, 2018. by guest www.bloodjournal.org From depletion of the subset in vivo. The results from these studies demonstrate that blockade of Ly49 inhibitory receptors augments NK cell-mediated antitumor effects and that strategies to block NK inhibitory receptor interactions may be of potential use in cancer therapy. Materials and methods MiceC57BL/6 (B6, H2 b ) mice were obtained from the Animal Production Area (National Cancer Institute at Frederick [NCI-Frederick], MD), and B6 severe combined immunodeficient scid/scid (SCID) mice were generously provided by Dr Robert H. Wiltrout (NCI-Frederick). All mice were kept in a specific pathogen-free condition and used at 8 to 12 weeks of age. Antibodies and generation of F(ab) 2 fragmentsAntimouse Fc␥R (2.4G2, rat immunoglobulin [Ig]-G2a), fluorescein isothiocyanate (FITC)-conjugated anti...