How does chronic activity modulation lead to global remodeling of proteins at synapses and synaptic scaling? Here we report a role of guanylate-kinase-associated-protein (GKAP; also known as SAPAP), a scaffolding molecule linking NMDA receptor-PSD-95 to Shank-Homer complexes, in these processes. Over-excitation removes GKAP from synapses via ubiquitin-proteasome system, while inactivity induces synaptic accumulation of GKAP in rat hippocampal neurons. The bi-directional changes of synaptic GKAP levels are controlled by specific CaMKII isoforms coupled to different Ca2+ channels. α-CaMKII activated by NMDA receptor phosphorylates Serine-54 of GKAP to induce poly-ubiquitination of GKAP. In contrast, β-CaMKII activation via L-type voltage-dependent calcium channel promotes GKAP recruitment by phosphorylating Serine-340 and Serine-384 residues, which uncouples GKAP from MyoVa motor complex. Remarkably, overexpressing GKAP turnover mutants not only hampers activity-dependent remodeling of PSD-95 and Shank but also blocks bi-directional synaptic scaling. Therefore, activity-dependent turnover of PSD proteins orchestrated by GKAP is critical for homeostatic plasticity.

The Rap family of small GTPases is implicated in the mechanisms of synaptic plasticity, particularly synaptic depression. Here we studied the role of Rap in neuronal morphogenesis and synaptic transmission in cultured neurons. Constitutively active Rap2 expressed in hippocampal pyramidal neurons caused decreased length and complexity of both axonal and dendritic branches. In addition, Rap2 caused loss of dendritic spines and spiny synapses, and an increase in filopodia-like protrusions and shaft synapses. These Rap2 morphological effects were absent in aspiny interneurons. In contrast, constitutively active Rap1 had no significant effect on axon or dendrite morphology. Dominant-negative Rap mutants increased dendrite length, indicating that endogenous Rap restrains dendritic outgrowth.The amplitude and frequency of a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-mediated miniature excitatory postsynaptic currents (mEPSCs) decreased in hippocampal neurons transfected with active Rap1 or Rap2, associated with reduced surface and total levels of AMPA receptor subunit GluR2. Finally, increasing synaptic activity with GABA A receptor antagonists counteracted Rap2's inhibitory effect on dendrite growth, and masked the effects of Rap1 and Rap2 on AMPAmediated mEPSCs. Rap1 and Rap2 thus have overlapping but distinct actions that potentially link the inhibition of synaptic transmission with the retraction of axons and dendrites.

While some convenience studies have found that optimism is protective for the risk of incident coronary heart disease (CHD) events, others have not. Optimism is separate from, but related to positive affect. We examined whether optimism was associated with a lower long-term risk of coronary heart disease (CHD) events in a large, population-based sample, independent of positive affect with 10 years follow-up after adjusting for positive affect.We examined whether optimism reduces the risk of incident CHD defined as fatal or nonfatal ischemic heart disease determined by hospital discharge codes or death certificates using ICD-9 codes (410-414) and ICD-10 codes (I21-I25). The population-based sample included the 1,739 adults (862 men and 877 women) in the 1995 Nova Scotia Health Survey. The study assessed optimism independent of Framingham cardiovascular risk factors, depressive symptoms, hostility, anxiety and positive affect; the latter assessed by the Center for Epidemiological Studies Depression Scale, Cook Medley Hostility scale, Spielberger Trait Anxiety Inventory, and objectively rated positive affect, respectively. Optimism was assessed using two questions from the revised Life Optimism Test questionnaire (LOT-R).There were 145 (8.3%) acute non-fatal or fatal ischemic heart disease events during the 14,916 person-years of observation. In a proportional hazards model controlling for age, sex, traditional cardiovascular risk factors and all the affect scales, those with moderate levels of optimism had reduced risk of incident CHD compared to those with high or low optimism levels (adjusted HR, 0.58; 95% CI 0.34-0.99; P=.047).In this large, population-based study, only moderate levels of optimism were associated with lower 10-year risk of incident CHD, independent of positive and negative affect.We recently published that positive affect was independently associated with decreased risk of 10-year incident coronary heart disease (CHD) in a large, population-based sample Questions arose about whether this reduction in risk was related to the experience of positive affect, or was due to an optimistic predisposition. We report here on whether or not

UDCA use was not associated with risk of colorectal cancer or dysplasia in adult PSC and IBD patients, but UDCA dose was a source of heterogeneity across studies. Subgroup analysis suggests a possible trend toward decreased colorectal cancer risk in low-to-medium-dose exposures. Additional study of UDCA treatments at low doses in PSC and IBD patients may be warranted.