Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability in people younger than 45 and is a significant public health concern. In addition to primary mechanical damage to cells and tissue, TBI involves additional molecular mechanisms of injury, termed secondary injury, that continue to evolve over hours, days, weeks, and beyond. The trajectory of recovery after TBI is highly unpredictable and in many cases results in chronic cognitive and behavioral changes. Acutely after TBI, there is an unregulated release of glutamate that cannot be buffered or cleared effectively, resulting in damaging levels of glutamate in the extracellular space. This initial loss of glutamate homeostasis may initiate additional changes in glutamate regulation. The excitatory amino acid transporters (EAATs) are expressed on both neurons and glia and are the principal mechanism for maintaining extracellular glutamate levels. Diffusion of glutamate outside the synapse due to impaired uptake may lead to increased extrasynaptic glutamate signaling, secondary injury through activation of cell death pathways, and loss of fidelity and specificity of synaptic transmission. Coordination of glutamate release and uptake is critical to regulating synaptic strength, long-term potentiation and depression, and cognitive processes. In this review, we will discuss dysregulation of extracellular glutamate and glutamate uptake in the acute stage of TBI and how failure to resolve acute disruptions in glutamate homeostatic mechanisms may play a causal role in chronic cognitive symptoms after TBI

Traumatic Brain Injury Induces Alterations in Cortical Glutamate Uptake without a Reduction in Glutamate Transporter-1 Protein Expression

We hypothesize that the primary mechanism for removal of glutamate from the extracellular space is altered after traumatic brain injury (TBI). To evaluate this hypothesis, we initiated TBI in adult male rats using a 2.0 atm lateral fluid percussion injury (LFPI) model. In the ipsilateral cortex and hippocampus, we found no differences in expression of the primary glutamate transporter in the brain (GLT-1) 24 h after TBI. In contrast, we found a decrease in glutamate uptake in the cortex, but not the hippocampus, 24 h after injury. Because glutamate uptake is potently regulated by protein kinases, we assessed global serine-threonine protein kinase activity using a kinome array platform. Twenty-five kinome array peptide substrates were differentially phoshorylated between LFPI and controls in the cortex, whereas 19 peptide substrates were differentially phosphorylated in the hippocampus (fold change ≥ ± 1.15). We identified several kinases as likely to be involved in acute TBI, including protein kinase B (Akt) and protein kinase C (PKC), which are well-characterized modulators of GLT-1. Exploratory studies using an inhibitor of Akt suggest selective activation of kinases in LFPI versus controls. Ingenuity pathway analyses of implicated kinases from our network model found apoptosis and cell death pathways as top functions in acute LFPI. Taken together, our data suggest diminished activity of glutamate transporters in the prefrontal cortex, with no changes in protein expression of the primary glutamate transporter GLT-1, and global alterations in signaling networks that include serine-threonine kinases that are known modulators of glutamate transport activity

An optometer device adapted to a phoropter

An optometer device adapted to a phoropte

A computational approach to managing coupled human–environmental systems: the POSEIDON model of ocean fisheries

Sustainable management of complex human–environment systems, and the essential services they provide, remains a major challenge, felt from local to global scales. These systems are typically highly dynamic and hard to predict, particularly in the context of rapid environmental change, where novel sets of conditions drive coupled socio-economic-environmental responses. Faced with these challenges, our tools for policy development, while informed by the past experience, must not be unduly constrained; they must allow equally for both the fine-tuning of successful existing approaches and the generation of novel ones in unbiased ways. We study ocean fisheries as an example class of complex human–environmental systems, and present a new model (POSEIDON) and computational approach to policy design. The model includes an adaptive agent-based representation of a fishing fleet, coupled to a simplified ocean ecology model. The agents (fishing boats) do not have programmed responses based on empirical data, but respond adaptively, as a group, to their environment (including policy constraints). This conceptual model captures qualitatively a wide range of empirically observed fleet behaviour, in response to a broad set of policies. Within this framework, we define policy objectives (of arbitrary complexity) and use Bayesian optimization over multiple model runs to find policy parameters that best meet the goals. The trade-offs inherent in this approach are explored explicitly. Taking this further, optimization is used to generate novel hybrid policies. We illustrate this approach using simulated examples, in which policy prescriptions generated by our computational methods are counterintuitive and thus unlikely to be identified by conventional frameworks

Women, autoimmunity, and cancer: a dangerous liaison between estrogen and activation-induced deaminase?

Why women are more susceptible to autoimmune diseases is not completely clear, but new data suggest that the hormone estrogen may play an important role. A new study now shows that estrogen activates the expression of activation-induced deaminase (AID), a protein that drives antibody diversification by deaminating cytosine in DNA to uracil. If estrogen increases the level of AID, increased mutations could transform benign antibodies into anti-self pariahs. AID might also contribute to cancer—particularly in breast tissue, which is highly responsive to estrogen—by introducing mutations and strand breaks into the genome

Poverty and Participation in Twenty-First Century Multicultural Britain

Peter Townsend argued that poverty could be scientifically measured as a ‘breakpoint’ within the income distribution below which participation collapses. This paper stands on Townsend's shoulders in measuring the level of poverty and participation by: (1) broadening his original measurement of participation; (2) using Structural Equation Modelling (SEM) in conjunction with a new dataset including 40,000 households (Understanding Society, 2011; 2013); and (3) taking into account the multi-cultural/ethnic nature of British society. We find that participation – defined as lack of deprivation, social participation and trust – reduces as income falls but stops doing so among the poorest 30 per cent of individuals. This may be indicating a minimum level of participation, a floor rather than a ‘breakpoint’ as suggested by Townsend, which has to be sustained irrespective of how low income is. Respondents with an ethnic minority background manifest lower levels of participation than white respondents but the relationship has a less linear pattern. Moreover, the floor detected for the overall population is also replicated when combining all respondents from ethnic groups

Dosage Effects of Cohesin Regulatory Factor PDS5 on Mammalian Development: Implications for Cohesinopathies

Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B−/− mice. While Pds5A−/− and Pds5B−/− mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A−/− or Pds5B−/− mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS