Faculty Bibliography

Long-lasting synaptic changes following information acquisition are critical steps for memory. In this process, long-term potentiation (LTP) is widely considered as one of the major cellular mechanisms modifying synaptic strength. It can be classified into early phase LTP (E-LTP) and late phase LTP (L-LTP) based on its duration. Using genetically modified mice, investigators have recognized the critical role of CaMKII in E-LTP and memory. However, its function in L-LTP, which is strongly dependent on gene transcription and protein synthesis, is still unclear. In this review, we discuss how different isoforms of CaMKII are coordinated to regulate gene expression in an activity-dependent manner, and thus contribute to L-LTP and memory. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

In this issue of Cell, Langen et al. use time-lapse multiphoton microscopy to show how Drosophila photoreceptor growth cones find their targets. Based on the observed dynamics, they develop a simple developmental algorithm recapitulating the highly complex connectivity pattern of these neurons, suggesting a basic framework for establishing wiring specificity.

Temporal sequences of transcription factors (tTFs) in Drosophila neural progenitors generate neuronal diversity. Mattar et al. (2015) identify Casz1/Castor as a late temporal identity factor in mouse retinal progenitors that is regulated by the early factor Ikzf1/Hunchback, thus generalizing the notion of tTFs.

BACKGROUND: Familial dysautonomia (FD, OMIM# 223900) is an autosomal recessive disease with features of impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. METHODS AND RESULTS: In a retrospective chart review of 665 FD patients, 8 patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person-years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person-years. Mean maximum creatine kinase (CK) level was 32,714 +/- 64,749 U/l. Three patients had a hip magnetic resonance imaging showing gluteal hyperintensities. CONCLUSIONS: Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities

Accumulation of toxic protein aggregates-amyloid-beta (Abeta) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Abeta accumulation has been hypothesized to result from an imbalance between Abeta production and clearance; indeed, Abeta clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Abeta is cleared from the brain. Extracellular Abeta deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Abeta (eAbeta) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAbeta from the brain, any alteration to their function could contribute to AD. An understanding of Abeta clearance might provide strategies to reduce excess Abeta deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Abeta.

Finding the components of cellular circuits and determining their functions systematically remains a major challenge in mammalian cells. Here, we introduced genome-wide pooled CRISPR-Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS), a key process in the host response to pathogens, mediated by the Tlr4 pathway. We found many of the known regulators of Tlr4 signaling, as well as dozens of previously unknown candidates that we validated. By measuring protein markers and mRNA profiles in DCs that are deficient in known or candidate genes, we classified the genes into three functional modules with distinct effects on the canonical responses to LPS and highlighted functions for the PAF complex and oligosaccharyltransferase (OST) complex. Our findings uncover new facets of innate immune circuits in primary cells and provide a genetic approach for dissection of mammalian cell circuits.

RATIONALE: The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. OBJECTIVES: This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. METHODS: TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. RESULTS: Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. CONCLUSIONS: This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.

Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-beta) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-beta inhibition using the anti-TGF-beta antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-beta inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.