Decoding Hippocampal Signaling Deficits After Traumatic Brain Injury

There are more than 3.17 million people coping with long-term disabilities due to traumatic brain injury (TBI) in the United States. The majority of TBI research is focused on developing acute neuroprotective treatments to prevent or minimize these long-term disabilities. Therefore, chronic TBI survivors represent a large, underserved population that could significantly benefit from a therapy that capitalizes on the endogenous recovery mechanisms occurring during the weeks to months following brain trauma. Previous studies have found that the hippocampus is highly vulnerable to brain injury, in both experimental models of TBI and during human TBI. Although often not directly mechanically injured by the head injury, in the weeks to months following TBI, the hippocampus undergoes atrophy and exhibits deficits in long-term potentiation (LTP), a persistent increase in synaptic strength that is considered to be a model of learning and memory. Decoding the chronic hippocampal LTP and cell signaling deficits after brain trauma will provide new insights into the molecular mechanisms of hippocampal-dependent learning impairments caused by TBI and facilitate the development of effective therapeutic strategies to improve hippocampal-dependent learning for chronic survivors of TBI

In situ measurements and model estimates of NO3 and NH4 uptake by different phytoplankton size fractions in the southern Benguela upwelling system.

Bulk measurements can be made of phytoplankton standing stocks on a quasi-synoptic scale but it is more difficult to measure rates of production and nutrient uptake. We present a method to estimate nitrogen uptake rates in productive coastal environments. We use observed phytoplankton cell size distributions and ambient nitrogen concentrations to calculate uptake rates of nitrate, ammonium and total nitrogen by different size fractions of diverse phytoplankton communities in a coastal upwelling system. The data are disaggregated into size categories, uptake rates are calculated and these uptake rates are reaggregated to obtain bulk estimates. The calculations are applied to 72 natural assemblages for which nitrogen uptake rates and particle size distributions were measured textit in situ . The calculated values of total N uptake integrated across all size classes are similar to those of textit in situ bulk measurements (N slope=0.90), (NH _ 4 slope=0.96) indicating dependence of NH _ 4 and total N uptake on ambient N concentrations and cell size distributions of the phytoplankton assemblages. NO _ 3 uptake was less well explained by cell size and ambient concentrations, but regressions between measured and estimated rates were still significant. The results suggest that net nitrogen dynamics can be quantified at an assemblage scale using size dependencies of Michaelis-Menten uptake parameters. These methods can be applied to particle size distributions that have been routinely measured in eutrophic systems to estimate and subsequently analyse variability in nitrogen uptake

Reactive oxygen species mediate activitydependent neuron-glia signaling in output fibers of the hippocampus

Nonsynaptic signaling is becoming increasingly appreciated in studies of activity-dependent changes in the nervous system. We investigated the types of neuronal activity that elicit nonsynaptic communication between neurons and glial cells in hippocampal output fibers. High-frequency, but not lowfrequency, action potential firing in myelinated CA1 axons of the hippocampus resulted in increased phosphorylation of the oligodendrocyte-specific protein myelin basic protein (MBP). This change was blocked by tetrodotoxin, indicating that axonally generated action potentials were necessary to regulate the phosphorylation state of MBP. Furthermore, scavengers of the reactive oxygen species superoxide and hydrogen peroxide and nitric oxide synthase inhibitors prevented activation of this neuron–glia signaling pathway. These results indicate that, during periods of increased neuronal activity in area CA1 of th

Is temperature an important variable in recovery after mild traumatic brain injury? [version 1; referees: 2 approved]

With nearly 42 million mild traumatic brain injuries (mTBIs) occurring worldwide every year, understanding the factors that may adversely influence recovery after mTBI is important for developing guidelines in mTBI management. Extensive clinical evidence exists documenting the detrimental effects of elevated temperature levels on recovery after moderate to severe TBI. However, whether elevated temperature alters recovery after mTBI or concussion is an active area of investigation. Individuals engaged in exercise and competitive sports regularly experience body and brain temperature increases to hyperthermic levels and these temperature increases are prolonged in hot and humid ambient environments. Thus, there is a strong potential for hyperthermia to alter recovery after mTBI in a subset of individuals at risk for mTBI. Preclinical mTBI studies have found that elevating brain temperature to 39°C before mTBI significantly increases neuronal death within the cortex and hippocampus and also worsens cognitive deficits. This review summarizes the pathology and behavioral problems of mTBI that are exacerbated by hyperthermia and discusses whether hyperthermia is a variable that should be considered after concussion and mTBI. Finally, underlying pathophysiological mechanisms responsible for hyperthermia-induced altered responses to mTBI and potential gender considerations are discussed

Inhibition of nitric oxide synthesis impairs two different forms of learning

Nitric oxide (NO), an intercellular messenger in the central nervous system of vertebrates, plays an important role in the establishment of synaptic plasticity. In order to investigate the role of NO and synaptic plasticity in learning, we injected rats and rabbits with the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) prior to training on two tests of learning. Rats treated with L.-NAME were impaired in learning a spatial learning task, while rabbits given the NO synthase inhibitor demonstrated learning deficits in the conditioned eyeblink response. The results support the hypothesis that NO plays a critical role in acquisition of two different forms of learning

Cytoplasmic polyadenylation element binding protein-dependent protein synthesis is regulated by calcium/calmodulin-dependent protein kinase II

Phosphorylation of cytoplasmic polyadenylation element binding protein (CPEB) regulates protein synthesis in hippocampal dendrites. CPEB binds the 3' untranslated region (UTR) of cytoplasmic mRNAs and, when phosphorylated, initiates mRNA polyadenylation and translation. We report that, of the protein kinases activated in the hippocampus during synaptic plasticity, calcium/calmodulin-dependent protein kinase II (CaMKII) robustly phosphorylated the regulatory site (threonine 171) in CPEB in vitro. In postsynaptic density fractions or hippocampal neurons, CPEB phosphorylation increased when CaMKII was activated. These increases in CPEB phosphorylation were attenuated by a specific peptide inhibitor of CaMKII and by the general CaM-kinase inhibitor KN-93. Inhibitors of protein phosphatase 1 increased basal CPEB phosphorylation in neurons; this was also attenuated by a CaM-kinase inhibitor. To determine whether CaM-kinase activity regulates CPEB-dependent mRNA translation, hippocampal neurons were transfected with luciferase fused to a 3' UTR containing CPE-binding elements. Depolarization of neurons stimulated synthesis of luciferase; this was abrogated by inhibitors of protein synthesis, mRNA polyadenylation, and CaMKII. These results demonstrate that CPEB phosphorylation and translation are regulated by CaMKII activity and provide a possible mechanism for how dendritic protein synthesis in the hippocampus may be stimulated during synaptic plasticity

Increased Phosphorylation of Myelin Basic Protein During Hippocampal Long‐Term Potentiation

: Hippocampal long‐term potentiation (LTP) is a long‐lasting and rapidly induced increase in synaptic strength. Previous experiments have determined that persistent activation of protein kinase C (PKC) contributes to the early maintenance phase of LTP (E‐LTP). Using the back‐phosphorylation method, we observed an increase in the phosphorylation of a 21‐kDa PKC substrate, termed p21, 45 min after LTP was induced in the CA1 region of the hippocampus. p21 was found to have the same apparent molecular weight as the 18.5‐kDa isoform of myelin basic protein (MBP) and was recognized by an antibody to MBP in western blotting and immunoprecipitation. Furthermore, p21 from control and potentiated hippocampal slices and purified MBP have identical phosphopeptide maps when back‐phosphorylated and then digested with either endoproteinase Lys‐C or endoproteinase Asp‐N, suggesting that p21 and MBP are identical proteins. As there was no observed change in the amount of MBP in LTP, the increase in MBP phosphorylation during LTP cannot be explained by a change in the amount of protein. From these experiments, we conclude that the phosphorylation of the 18.5‐kDa isoform of MBP is increased during E‐LTP

Activated c-Jun N-Terminal Kinase Is Required for Axon Formation

A critical transition in neuron development is formation of the axon, which establishes the polarized structure of the neuron that underlies its entire input and output capabilities. The morphological events that occur during axonogenesis have long been known, yet the molecular determinants underlying axonogenesis remain poorly understood. We demonstrate here that axonogenesis requires activated c-Jun N-terminal kinase (JNK). JNK is expressed throughout the neuron, but its phosphorylated, activated form is highly enriched in the axon. In young axons, activated JNK forms a proximodistal gradient of increasing intensity, beginning at about the point where the axon exceeds the lengths of the other neurites (minor processes). Treatment with SP600125, a specific inhibitor of JNK, reversibly inhibits axonogenesis but does not prevent the formation of minor processes or their differentiation into dendrites (based on their immunostaining with marker proteins). Expression of a dominant-negative construct against JNK similarly prevents axonogenesis. Investigation of JNK targets revealed that activating transcription factor-2 is phosphorylated under normal conditions in neurons, and its phosphorylation is significantly attenuated after JNK inhibition. These results demonstrate that activated JNK is required for axonogenesis but not formation of minor processes or development of dendrites