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The level of arousal in mammals is correlated with metabolic state and specific patterns of cortical neuronal responsivity. In particular, rhythmic transitions between periods of high activity (up phases) and low activity (down phases) vary between wakefulness and deep sleep/anesthesia. Current opinion about changes in cortical response state between sleep and wakefulness is split between neuronal network-mediated mechanisms and neuronal metabolism-related mechanisms. Here, we demonstrate that slow oscillations in network state are a consequence of interactions between both mechanisms. Specifically, recurrent networks of excitatory neurons, whose membrane potential is partly governed by ATP--modulated potassium ([K.sub.ATP]) channels, mediate response-state oscillations via the interaction between excitatory network activity involving slow, kainate receptor-mediated events and the resulting activation of ATP-dependent homeostatic mechanisms. These findings suggest that [K.sub.ATP] channels function as an interface between neuronal metabolic state and network responsivity in mammalian cortex. glutamate | slow-wave oscillation | potassium channel | rhythm

Metabotropic glutamate receptors (mGluRs) in hippocampus are involved in the formation of long-term potentiation (LTP) and depotentiation. The mGluRs are essential to trigger LTP when slices are in a deconditioned state. The mGluRs trigger a molecular switch that removes the need for mGluR stimulation during LTP induction.

The hippocampus receives an extensive cholinergic input from the medial septal nucleus that ramifies throughout all layers and plays a pivotal modulatory role in cognitive function. Although the pharmacological effects of exogenous application of cholinergic agonists have been extensively studied in hippocampal neurons, much less is known about the effects of synaptically released acetylcholine (ACh). In this respect, most studies have focused on the cholinergic afferent input to pyramidal neurons that produces a characteristically slow depolarizing synaptic response mediated by activation of muscarinic ACh receptors (mAChRs). Here we report that cholinergic afferent stimulation also elicits atropine-sensitive synaptic potentials in hippocampal CA1 interneurons but, in contrast to synaptic responses in pyramidal neurons, these are highly diverse in waveform, although can still be classified into five distinct subtypes. The most common response type (i) 64% of cells) consisted of a slow sustained membrane potential depolarization. The other 36% of responses could be subdivided into responses comprising of (ii) a biphasic membrane potential change in which an initial slow hyperpolarization subsequently transforms into a slow depolarization (20%), (iii) a pure, slow hyperpolarization (13%), and (iv) an oscillatory response persisting for several seconds (2%). Interestingly, there were also interneurons totally insensitive to both synaptic and pharmacological cholinergic challenge. Morphological investigation of recorded cells revealed no obvious correlation between responsiveness to cholinergic afferent stimulation and dendritic and axonal arborization. The current study suggests that synaptic release of ACh results in a complex and differential mAChR-mediated modulation of cellular excitability within the hippocampal interneuron population. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Learning and memory involve complex changes in neuronal excitability including long-lasting synaptic plasticity of glutamatergic synapses. The observation that the neuropeptide galanin affects performance in a number of behavioural models predicts that galanin should affect synaptic processes underlying learning. The present study in rat and mouse hippocampal slices now demonstrates that galanin inhibits long-term potentiation induced by both tetanic and theta-burst stimulation in both apical and basal dendrites of CA1 pyramidal neurones but does not affect long-term depression. This selective effect on long-term potentiation does not appear to be mediated through inhibition of N-methyl-D-aspartate or metabotropic glutamate receptor function, but likely resides downstream of receptor activation, possibly at the level of the kinase cascade that converts short-term into long-term potentiation.Our results indicate possible mechanisms by which the neuropeptide galanin may act at the molecular level to influence learning and memory in vertebrates. [Copyright &y& Elsevier]

Objectives: There has been debate regarding the level of sarcoplasmic reticulum (SR) Ca2+ ATPase protein in heart failure. We have used the SR Ca2+ ATPase inhibitor thapsigargin to investigate the functional contribution of this uptake system to contraction and relaxation in myocytes from failing and non-failing human ventricle. Methods: Myocytes were isolated from 28 failing and 18 non-failing ventricles and stimulated at 0.2 Hz, 32°C in Krebs-Henseleit solution. Contraction amplitude and speed were compared before and after treatment with 1 μmol/l thapsigargin for 20 min to deplete SR Ca2+ stores. Results: Initial beat duration was longer in myocytes from failing hearts. Addition of thapsigargin significantly prolonged the beat in myocytes from both groups, but the increase was greater in non-failing hearts (beat duration increased by 0.79 ± 0.12 s in myocytes from non-failing hearts compared with 0.37 ± 0.12 s in those from failing, P < 0.02). The contraction amplitude increased at high stimulation frequencies in myocytes from non-failing hearts (from 2.6% shortening at 0.1 Hz to 4.6% at 1 Hz, P < 0.001, n = 9), but not in those from failing hearts (1.8% at 0.1 Hz compared with 1.7% at 1 Hz, n = 5). Thapsigargin abolished the positive staircase in the non-failing, but had no effect in the failing group. Contraction amplitude following a rest interval was significantly depressed relative to steady-state levels in myocytes from the non-failing hearts (44.8 ± 10.3% at 3 min), but not in failing (102 ± 18%, P < 0.01 compared to non-failing at 3 min). Following thapsigargin treatment, there were no longer significant differences between failing and non-failing myocytes in the time course of the beat, frequency response or post-rest behaviour. Conclusion: The differences between myocytes from failing and non-failing hearts were reduced by inhibition of SR function. These results are consistent with the hypothesis that the initial differences had been due to decreased SR Ca2+ uptake. [ABSTRACT FROM PUBLISHER]

The contractile response to β-adrenoceptor stimulation has been found to be reduced in single myocytes from failing human ventricle. A portion of that reduction was statistically related to the age of the patient. We have developed a method for obtaining viable contracting myocytes from small biopsies of human ventricle, enabling experiments to be performed on non-failing left ventricle from patients undergoing coronary artery surgery. These subjects are generally in an older age range than those we have previously obtained from donor hearts. The present study compares responses to isoproterenol and high Ca2+ between myocytes from older (>50 years, n = 8) and younger (<40 years, n = 5) subjects. Myocytes from older patients did not differ in their contraction amplitude (10.7 ± 1.0 cf. 10.8 ± 1.1% cell shortening), or contraction and relaxation velocities in high Ca2+ at a driving frequency of 0.2 Hz (32 °C). The sensitivity to isoproterenol, as determined from the EC50 value (concentration for half-maximal effect), was also similar between age groups (1.16 ± 0.64 nM young, cf. 2.76 ± 2.0 nM old), although higher than in myocytes from failing hearts (22.3 ± 7.5 nM, n = 11). However, for the older group there was a significant depression in maximum contraction amplitude with isoproterenol (8.5 ± 0.6 cf. 11.5 ± 1.0% cell shortening, P < 0.05) and in the ratio between this and the maximum Ca2+ response (isoproterenol/Ca2+ ratio, 0.79 ± 0.05 cf. 1.16 ± 0.12, P < 0.05). Concomitantly, the maximum contraction and relaxation velocities achieved in the presence of isoproterenol were also depressed in older subjects (P < 0.02 for both). We conclude that age and/or coronary disease with unimpaired left ventricular function selectively reduces the maximum effect of isoproterenol but not the concentration at which this occurs. [ABSTRACT FROM PUBLISHER]

States that during high-frequency transmission, gamma-aminobutyric acid (GABA) depresses its own release by an action on GABA B autoreceptors, which permits sufficient N-methyl-D-aspartate receptor activation for the induction of long-term potentiation (LTP). Methods; Results; Discussion.

Abstract: One of the major neuropathological hallmarks in Alzheimer’s disease (AD) is the loss of cholinergic neurones of the nucleus basalis of Meynert (NbM). This consistent finding gave rise to the ‘cholinergic’ hypothesis of AD and lead to the subsequent development of acetylcholinesterase (AChE) inhibitors; the first class of drug to be approved for the treatment of AD. However, several studies have questioned the efficacy of using AChE inhibitors in AD. In this study we have investigated the ability of two AChE inhibitors, donepezil (Aricept) and physostigmine, to induce gamma oscillatory activity in rat hippocampal slices; network activity believed to play a role in higher cognitive function. We report here that donepezil is capable of inducing gamma oscillations in region CA3 of rat hippocampal slices, which may contribute to its procognitive action. However, donepezil-induced gamma oscillations are weak in comparison to physostigmine. We also explore the activity of novel agents with known procognitive activity, and show that one such agent, the M1 muscarinic acetylcholine receptor agonist, 77-LH-28-1, can significantly enhance donepezil-induced gamma oscillations. These data support the notion that it should be possible to find a more efficacious AChE inhibitor or an adjunctive approach, to provide a better therapeutic intervention in AD. [ABSTRACT FROM AUTHOR]

GABAB receptor subunits are widely expressed on neurons throughout the CNS, at both pre- and postsynaptic sites, where they mediate the late, slow component of the inhibitory response to the major inhibitory neurotransmitter GABA. The existence of functional GABAB receptors on nonneuronal cells has been reported previously, although the molecular composition of these receptors has not yet been described. Here we demonstrate for the first time, using immunohistochemistry the expression of GABAB1a, GABAB1b, and GABAB2 on nonneuronal cells of the rat CNS. All three principle GABAB receptor subunits were expressed on these cells irrespective of whether they had been cultured or found within brain tissue sections. At the ultrastructural level GABAB receptor subunits were expressed on astrocytic processes surrounding both symmetrical and assymetrical synapses in the CA1 subregion of the hippocampus. In addition, GABAB1a, GABAB1b, and GABAB2 receptor subunits were expressed on activated microglia in culture but were not found on myelin forming oligodendrocytes in the white matter of rat spinal cord. Together these data demonstrate that the obligate subunits of functional GABAB receptors are expressed in astrocytes and microglia in the rat CNS. [Copyright &y& Elsevier]

Abstract The dynamics of nutrients, phytoplankton, zooplankton and water clarity of the iconic Great Barrier Reef World Heritage Area (GBRWHA) are influenced by seasonal variation in coastal and oceanic conditions, and anthropogenic inputs. We use the 3-dimensional coupled catchment-hydrodynamic-sediment-wave-optical-biogeochemical eReefs model to hindcast nutrient and planktonic responses to changes in seasonal and annual variability over a six-year period (2011–2016). In this paper we present a comparison of the eReefs model conducted against a range of in situ observations that included 24 water quality moorings, 2 nutrient sampling programs (with a total of 18 stations) and time-series of taxon-specific plankton abundance. At 14 near-coastal stations the simulated chlorophyll a (Chl a), when compared with chlorophyll extractions from water samples, had an average root mean square (RMS) error of 0.30 mg m−3 and a Willmott index of 0.59. For the same sites, simulated turbidity, when compared with turbidity sensors, had a Willmott index of 0.58 and simulated nitrate + nitrite had a Willmott index of 0.41 when compared with tri-annual water samples. Comparison with a spatially-resolved statistical model of zooplankton based on >900 observations in the region showed similarities in the relationship and spatial distribution of simulated and observed biomass, where both show zooplankton biomass is greatest inshore, biomass is highest around shallow reef areas and in the southern and central GBRWHA, and greater in summer than winter. Additionally, we investigate planktonic and nutrient responses to climatic variation. The first two years of the simulation coincided with La Niña events that drive greater than average winds, rainfall and river discharge. Throughout all years, simulated Chl a increases from north to south and from outer to inner coastal regions. Dissolved inorganic nitrogen, primary production and phytoplankton biomass were higher during La Niña in inshore and mid-shelf waters, while offshore regions were similar in all years from 2011 to 2016. Simulated Secchi depth was deeper offshore and decreased from offshore to inner coastal regions and from north to south. The eReefs simulation contributes to the understanding at a high spatial and temporal resolution of where and how nutrients and plankton originate and interact within the Great Barrier Reef. Highlights • Use of a 3D-catchment-hydrodynamic-sediment-wave-optical-biogeochemical model • Model encompasses the 2300 km long Great Barrier Reef from coast to Coral Sea. • Comparison of observations with simulated plankton & nutrients • Observations include remote sensing, moorings and water samples. • Simulated nutrients and plankton show realistic seasonal and interannual variation. [ABSTRACT FROM AUTHOR]

Abstract: Clinically, amantadine and memantine are drugs whose therapeutic utility is linked to their ability to block N-methyl-D-aspartate receptors (NMDARs) in a voltage-dependent manner. Nevertheless many studies that have characterized the pharmacological actions of amantadine and memantine have done so in the absence of physiological levels of Mg2+ ions. This study quantifies the extent to which Mg2+ alters the potency of the block produced by both amantadine and memantine at human recombinant GluN1/GluN2A NMDARs. Human recombinant GluN1/GluN2A NMDARs were expressed in Xenopus laevis oocytes and two-electrode voltage-clamp recordings were made at −80, −60 and −40mV to quantify amantadine and memantine block in the absence and presence of Mg2+. Amantadine and memantine blocked human GluN1/GluN2A NMDARs in a voltage-dependent manner with IC50 values (at −80mV) of 49±6μM (n =7) and 1.0±0.3μM (n =7), respectively. In the presence of Mg2+ (1mM) the equivalent IC50 values were 165±10μM (n =6) and 6.6±0.3μM (n =5). Similarly in the presence of amantadine or memantine the potency of Mg2+ in blocking GluN1/GluN2A NMDARs was reduced. The decrease in the potencies of both amantadine and memantine in the presence of physiological concentrations of Mg2+ indicates that other targets (e.g. α7-nicotinic acetylcholine receptors and 5-HT3 receptors) in addition to NMDARs may well be sites of the therapeutic action of these channel blockers. [ABSTRACT FROM AUTHOR]

Abstract: Exposure to an enriched environment promotes neurochemical, structural and neurophysiological changes in the brain and is associated with enhanced synaptic plasticity and improved hippocampal-dependent learning. Using a global proteomics-based approach we have now been able to reveal the altered expression of a diverse range of hippocampal proteins following exposure to an enriched environment. Male Hooded Lister rats (8 weeks) were subjected to a 6-week regimen in which they were housed in either non-enriched (open field) or enriched conditions (toys, wheels etc.). Whole protein extracts from stratum pyramidale and stratum radiatum of area CA1 were then isolated and subjected to differential gel electrophoresis [McNair K, Davies CH, Cobb SR (2006) Plasticity-related regulation of the hippocampal proteome. Eur J Neurosci 23(2):575–580]. Of the 2469 resolvable protein spots detected in this study, 42 spots (1.7% of the detectable proteome) derived from predominantly somatic fractions and 32 proteins spots from dendritic fractions (1.3% of detectable proteome) were significantly altered in abundance following exposure to an enriched environment (somatic: 14 increased/28 decreased abundance, range −1.5 to +1.4-fold change; dendritic: 16 increased, 16 decreased abundance, range −1.6 to +3.0-fold change). Following in-gel tryptic digestion and Maldi-Tof/Q-star mass spectrometry, database searching revealed the identity of 50 protein spots displaying environmental enrichment-related modulation of expression. Identified proteins belonged to a variety of functional classes with gene ontology analysis revealing the majority (>70%) of regulated proteins to be part of the energy metabolism, cytoplasmic organization/biogenesis and signal transduction processes. [Copyright &y& Elsevier]

Several psychiatric diseases, including schizophrenia, are thought to have a developmental aetiology, but to date no clear link has been made between psychiatric disease and a specific developmental process. LPA1 is a Gi-coupled seven transmembrane receptor with high affinity for lysophosphatidic acid. Although LPA1 is expressed in several peripheral tissues, in the nervous system it shows relatively restricted temporal expression to neuroepithelia during CNS development and to myelinating glia in the adult. We report the detailed neurological and behavioural analysis of mice homozygous for a targeted deletion at the lpa1 locus. Our observations reveal a marked deficit in prepulse inhibition, widespread changes in the levels and turnover of the neurotransmitter 5-HT, a brain region-specific alteration in levels of amino acids, and a craniofacial dysmorphism in these mice. We suggest that the loss of LPA1 receptor generates defects resembling those found in psychiatric disease. [Copyright &y& Elsevier]

Neuronal networks of the hippocampal CA3 region generate stereotyped patterns of electrical activity in response to activation of metabotropic glutamate receptors (mGluRs) or muscarinic acetylcholine receptors (mAChRs) that consist of intermittent episodes of prolonged oscillatory activity. In light of the slow kinetics of such network responses, we investigated the possible contribution of the hyperpolarisation-activated inward current (Ih) in the generation and maintenance of hippocampal oscillatory states. Hippocampal ‘mini-slice’ experiments in which the main subfields of the hippocampus were isolated by transection of the connecting afferents revealed that the CA3 region was the primary generator of both mGluR and mAChR-mediated network responses. Subsequent patch-clamp experiments confirmed the presence of a prominent hyperpolarisation-activated inward current in the principal cells of the CA3 region that was sensitive to caesium chloride and the selective Ih blocker ZD-7288.Furthermore, in the presence of mAChR or mGluR agonists these cells exhibited a slow membrane potential oscillation that was independent of AMPA receptor-mediated synaptic transmission. Blockade of Ih suppressed this oscillation as well as mGluR and mAChR-induced theta based intermittent network oscillatory behaviour. These data support the idea that the Ih pacemaker current is important in the generation of patterned neuronal activities in the hippocampus. [Copyright &y& Elsevier]