Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischemia and acidosis in hippocampal CA1 neurons

The CA1 region of the hippocampus is particularly vulnerable to ischemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca2+ -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a) which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischemic neuronal death and to physiologically induced LTP. This raises the question - does ASIC1a activation drive the post-ischemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPN) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection

Parameter identification in groundwater flow: a feasibility study

A set of first-order differential state equations is developed from taking finite differences of the partial differential equation that describes groundwater flow during a pump-drawdown test. The number of states in the model is a direct function of the number of discrete spatial segments used in the approximate model. This number of states is studied to determine a reasonably low-order model that preserves the accuracy of resulting simulations when compared with an available analytical solution. The resulting reduced-order model is then used in an extended Kalman filter for combined state and parameter estimation. This report summarizes work done in a recent pilot study to demonstrate the feasibility of these techniques in groundwater research and points the way toward other approaches to this problem area now under study

Simplified groundwater flow modeling: an application of Kalman filter based identification

The need exists for methods to simplify groundwater contaminant transport models. Reduced-order models are needed in risk assessments for licensing and regulating long-term nuclear waste repositories. Such models will be used in Monte Carlo simulations to generate probabilities of nuclear waste migration in aquifers at candidate repository sites in the United States. In this feasibility study we focused on groundwater flow rather than contaminant transport because the flow problem is more simple. A pump-drawdown test is modeled with a reduced-order set of ordinary differential equations obtained by differencing the partial differential equation. We determined the accuracy of the reduced model by comparing it with the analytic solution for the drawdown test. We established an accuracy requirement of 2% error at the single observation well and found that a model with only 21 states satisfied that criterion. That model was used in an extended Kalman filter with synthesized measurement data from one observation well to identify transmissivity within 1% error and storage coefficient within 10% error. We used several statistical tests to assess the performance of the estimator/identifier and found it to be satisfactory for this application

Distribution and abundance of skates (Bathyraja spp.) on the Kerguelen Plateau through the lens of the toothfish fisheries

Three species of skate, Bathyraja eatonii, B. irrasa and B. murrayi, are commonly taken as incidental by-catch in Patagonian toothfish (Dissostichus eleginoides) longline and trawl fisheries, and the mackerel icefish (Champsocephalus gunnari) trawl fishery on the Kerguelen Plateau (KP) in the southern Indian Ocean. Data from fishery observations for 1997–2014 shows that the three skates were widely distributed across the Kerguelen Plateau, showing different spatial distributions, linked mainly with depth. Off Heard Island and McDonald Islands (HIMI), in the southern part of the KP, B. eatonii and B. irrasa were most abundant to the north and northwest of Heard Island, out to the edge of the Australian Exclusive Economic Zone (EEZ), and were caught down to depths of 1790 m and 2059 m respectively. The smallest species, B. murrayi, occurred mainly in the shallower waters down to 550 m, and was most abundant to the north and northeast, close to Heard Island. Around Kerguelen Islands, in the northern part of the KP, skates were most abundant between the 500 m and 1000 m contours circling and extending from the islands.Catch rates were modelled using zero-inflated GAMs and GLMs. The catch rates of skates from the trawl fisheries in the Australian EEZ surrounding Heard Island and McDonald Islands have shown little evidence of depletion on the main trawl fishing grounds, although there is evidence of a decrease in the average total length of B. eatonii. The marine reserves and the conservation measures employed by the Commission for the Conservation of Antarctic Marine Living Resources in the HIMI fisheries, appear to provide effective protection for the skates, at least in the shallower waters where the trawl fisheries operate. B. irrasa taken in the deeper waters where longline fishing occurs have shown a slight decline in catch rate over the years of the HIMI fishery. Although all skates are returned to the water from this fishery, survival rates are unknown and careful monitoring should continue to assess the status of these stocks. There appears to be little change in the abundance of the skate species at Kerguelen in the time period.This study provides the first review of skate by-catch across both the HIMI and Kerguelen fisheries. Ongoing monitoring of species specific by-catch levels and further research to determine the important life history parameters of these species are required, particularly for B. irrasa which is taken in both trawl and longline fisheries

Cornichons modify channel properties of recombinant and glial AMPA receptors

Ionotropic glutamate receptors, which underlie a majority of excitatory synaptic transmission in the CNS, associate with transmembrane proteins that modify their intracellular trafficking and channel gating. Significant advances have been made in our understanding of AMPA-type glutamate receptor (AMPAR) regulation by transmembrane AMPAR regulatory proteins. Less is known about the functional influence of cornichons-unrelated AMPAR-interacting proteins, identified by proteomic analysis. Here we confirm that cornichon homologs 2 and 3 (CNIH-2 and CNIH-3), but not CNIH-1, slow the deactivation and desensitization of both GluA2-containing calciumimpermeable and GluA2-lacking calcium-permeable (CP)AMPARsexpressed in tsA201 cells. CNIH-2 and -3 also enhanced the glutamate sensitivity, single-channel conductance, and calcium permeability of CP-AMPARs while decreasing their block by intracellular polyamines. We examined the potential effects of CNIHs on native AMPARs by recording from rat optic nerve oligodendrocyte precursor cells (OPCs), known to express a significant population of CP-AMPARs. These glial cells exhibited surface labeling with an anti-CNIH-2/3 antibody. Two features of their AMPAR-mediated currents-the relative efficacy of the partial agonist kainate (I KA/I Glu ratio 0.4) and a greater than fivefold potentiation of kainate responses by cyclothiazide-suggest AMPAR association with CNIHs. Additionally, overexpression of CNIH-3 in OPCs markedly slowed AMPAR desensitization. Together, our experiments support the view that CNIHs are capable of altering key properties of AMPARs and suggest that they may do so in glia. © 2012 the authors

The first 50 years of molecular pharmacology

In this Perspective, former and current editors of Molecular Pharmacology, together with the guest editors for this 50th Anniversary Issue, provide a historical overview of the journal since its founding in 1965. The substantial impact that Molecular Pharmacology has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the journal, Molecular Pharmacology today remains an outstanding venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biologic targets

The effect of intracellular Ca2+ on GABA-activated currents in cerebellar granule cells in culture

The patch clamp technique was used to study the effects of intracellular free calcium ([Ca2+]i) on GABAA-evoked whole-cell and single channel currents of cultured cerebellar granule cells. Changes in [Ca2+]i were obtained by adding to the extracellular solution the calcium ionophore A23187 (2 \u3bcm). The relationship between [Ca2+]i and [Ca2+]O in the presence or absence of A23187 was assessed using fluorimetric measurements from Fura-2 loaded cells. In 2 m m [Ca2+]o and A23187, [Ca2+]i was about 1.5 \u3bcm, whereas in the absence of A23187 it was about 250 n m. In whole-cell experiments (symmetrical chloride concentrations) at -50 mV, GABA (0.5 \u3bcm) evoked inward currents that did not desensitize. Bath application of A23187 significantly reduced the steady-state amplitude of GABA currents by 37 \ub1 6%. Single channel currents activated by GABA (0.5 \u3bcm) were also recorded in the outside-out configuration of the patch clamp technique. Kinetic analysis of single channel events revealed that A23187 significantly increased the long closed time constant (\u3c4c3) without affecting the open time constants (\u3c4o1 and \u3c4o2) or the short and medium closed time constants (\u3c4c1 and \u3c4c2). Moreover, application of A23187 induced a significant reduction of burst duration (\u3c4b). We conclude that a rise in [Ca2+]i by A23187 may decrease the binding affinity of GABA for the GABAA receptor. We thank Prof. D. Colquhoun for critical reading of the manuscript and Drs. F. Vittur and M. Fragonas for allowing us the use of the spectrofluorimeter. \ua9 1994 Springer-Verlag New York Inc