Background synaptic activity in rat entorhinal cortical neurones:differential control of transmitter release by presynaptic receptors

The entorhinal cortex (EC) is a key brain area controlling both hippocampal input and output via neurones in layer II and layer V, respectively. It is also a pivotal area in the generation and propagation of epilepsies involving the temporal lobe. We have previously shown that within the network of the EC, neurones in layer V are subject to powerful synaptic excitation but weak inhibition, whereas the reverse is true in layer II. The deep layers are also highly susceptible to acutely provoked epileptogenesis. Considerable evidence now points to a role of spontaneous background synaptic activity in control of neuronal, and hence network, excitability. In the present article we describe results of studies where we have compared background release of the excitatory transmitter, glutamate, and the inhibitory transmitter, GABA, in the two layers, the role of this background release in the balance of excitability, and its control by presynaptic auto- and heteroreceptors on presynaptic terminals. © The Physiological Society 2004.

The role of cannabinoid receptors in modulation of GABAergic neurotransmission in the rat medial entorhinal cortex in vitro

Type 1 cannabinoid receptors (CB1R) have a well established role in modulating GABAergic signalling with the central nervous system, and are thought to be the only type present at GABAergic presynaptic terminals. In the medial entorhinal cortex (mEC), some cortical layers show high levels of ongoing GABAergic signalling (namely layer II) while others show relatively low levels (layer V). Using whole-cell patch clamp techniques, I have, for the first time, demonstrated the presence of functional CB1R in both deep and superficial layers of the mEC. Furthermore, using a range of highly specific ligands for both CB1R and CB2R, I present strong pharmacological evidence for CB2Rs being present in both deep and superficial layers of the mEC in the adult rat brain. In brain slices taken at earlier points in CNS development (P8-12), I have shown that while both CB1R and CB2R specific ligands do modulate GABAergic signalling at early developmental stages, antagonists/ inverse agonists and full agonists have similar effects, and serve only to reduce GABAergic signalling. These data suggest that the full cannabinoid signalling mechanisms at this early stage in synaptogenesis are not yet in place. During these whole-cell studies, I have developed and refined a novel recording technique, using an amantidine derivative (IEM1460) which allows inhibitory postsynaptic currents to be recorded under conditions in which glutamate receptors are not blocked and network activity remains high. Finally I have shown that bath applied CB1 and CB2 receptor antagonists/ inverse agonists are capable of modulating kainic acid induced persistent oscillatory activity in mEC. Inverse agonists suppressed oscillatory activity in the superficial layers of the mEC while it was enhanced in the deeper layers. It seems likely that cannabinoid receptors modulate the inhibitory neuronal activity that underlies network oscillations.

Mobility of NMDA autoreceptors but not postsynaptic receptors at glutamate synapses in the rat entorhinal cortex

NMDA receptors (NMDAr) are known to undergo recycling and lateral diffusion in postsynaptic spines and dendrites. However, NMDAr are also present as autoreceptors on glutamate terminals, where they act to facilitate glutamate release, but it is not known whether these receptors are also mobile. We have used functional pharmacological approaches to examine whether NMDA receptors at excitatory synapses in the rat entorhinal cortex are mobile at either postsynaptic sites or in presynaptic terminals. When NMDAr-mediated evoked EPSCs (eEPSCs) were blocked by MK-801, they showed no evidence of recovery when the irreversible blocker was removed, suggesting that postsynaptic NMDAr were relatively stably anchored at these synapses. However, using frequency-dependent facilitation of AMPA receptor (AMPAr)-mediated eEPSCs as a reporter of presynaptic NMDAr activity, we found that when facilitation was blocked with MK-801 there was a rapid (similar to 30-40 min) anomalous recovery upon removal of the antagonist. This was not observed when global NMDAr blockade was induced by combined perfusion with MK-801 and NMDA. Anomalous recovery was accompanied by an increase in frequency of spontaneous EPSCs, and a variable increase in frequency-facilitation. Following recovery from blockade of presynaptic NMDAr with a competitive antagonist, frequency-dependent facilitation of AMPAr-mediated eEPSCs was also transiently enhanced. Finally, an increase in frequency of miniature EPSCs induced by NMDA was succeeded by a persistent decrease. Our data provide the first evidence for mobility of NMDAr in the presynaptic terminals, and may point to a role of this process in activity-dependent control of glutamate release.

Functional presynaptic HCN channels in the rat globus pallidus

Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are expressed postsynaptically in the rodent globus pallidus (GP), where they play several important roles in controlling GP neuronal activity. To further elucidate the role of HCN channels in the GP, immunocytochemical and electrophysiological approaches were used to test the hypothesis that HCN channels are also expressed presynaptically on the local axon collaterals of GP neurons. At the electron microscopic level, immunoperoxidase labelling for HCN1 and HCN2 was localized in GP somata and dendritic processes, myelinated and unmyelinated axons, and axon terminals. One population of labelled terminals formed symmetric synapses with somata and proximal dendrites and were immunoreactive for parvalbumin, consistent with the axon collaterals of GABAergic GP projection neurons. In addition, labelling for HCN2 and, to a lesser degree, HCN1 was observed in axon terminals that formed asymmetric synapses and were immunoreactive for the vesicular glutamate transporter 2. Immunogold labelling demonstrated that HCN1 and HCN2 were located predominantly at extrasynaptic sites along the plasma membrane of both types of terminal. To determine the function of presynaptic HCN channels in the GP, we performed whole-cell recordings from GP neurons in vitro. Bath application of the HCN channel blocker ZD7288 resulted in an increase in the frequency of mIPSCs but had no effect on their amplitude, implying that HCN channels tonically regulate the release of GABA. Their presence, and predicted role in modulating transmitter release, represents a hitherto unidentified mechanism whereby HCN channels influence the activity of GP neurons. © The Authors (2007).

Depression of glutamate and GABA release by presynaptic GABAB receptors in the entorhinal cortex in normal and chronically epileptic rats

Presynaptic GABAB receptors (GABABR) control glutamate and GABA release at many synapses in the nervous system. In the present study we used whole-cell patch-clamp recordings of spontaneous excitatory and inhibitory synaptic currents in the presence of TTX to monitor glutamate and GABA release from synapses in layer II and V of the rat entorhinal cortex (EC)in vitro. In both layers the release of both transmitters was reduced by application of GABABR agonists. Quantitatively, the depression of GABA release in layer II and layer V, and of glutamate release in layer V was similar, but glutamate release in layer II was depressed to a greater extent. The data suggest that the same GABABR may be present on both GABA and glutamate terminals in the EC, but that the heteroreceptor may show a greater level of expression in layer II. Studies with GABABR antagonists suggested that neither the auto- nor the heteroreceptor was consistently tonically activated by ambient GABA in the presence of TTX. Studies in EC slices from rats made chronically epileptic using a pilocarpine model of temporal lobe epilepsy revealed a reduced effectiveness of both auto- and heteroreceptor function in both layers. This could suggest that enhanced glutamate and GABA release in the EC may be associated with the development of the epileptic condition. Copyright © 2006 S. Karger AG.

Transmission of image data over digital networks involving mobile terminals

There is a growing demand for data transmission over digital networks involving mobile terminals. An important class of data required for transmission over mobile terminals is image information such as street maps, floor plans and identikit images. This sort of transmission is of particular interest to the service industries such as the Police force, Fire brigade, medical services and other services. These services cannot be applied directly to mobile terminals because of the limited capacity of the mobile channels and the transmission errors caused by the multipath (Rayleigh) fading. In this research, transmission of line diagram images such as floor plans and street maps, over digital networks involving mobile terminals at transmission rates of 2400 bits/s and 4800 bits/s have been studied. A low bit-rate source encoding technique using geometric codes is found to be suitable to represent line diagram images. In geometric encoding, the amount of data required to represent or store the line diagram images is proportional to the image detail. Thus a simple line diagram image would require a small amount of data. To study the effect of transmission errors due to mobile channels on the transmitted images, error sources (error files), which represent mobile channels under different conditions, have been produced using channel modelling techniques. Satisfactory models of the mobile channel have been obtained when compared to the field test measurements. Subjective performance tests have been carried out to evaluate the quality and usefulness of the received line diagram images under various mobile channel conditions. The effect of mobile transmission errors on the quality of the received images has been determined. To improve the quality of the received images under various mobile channel conditions, forward error correcting codes (FEC) with interleaving and automatic repeat request (ARQ) schemes have been proposed. The performance of the error control codes have been evaluated under various mobile channel conditions. It has been shown that a FEC code with interleaving can be used effectively to improve the quality of the received images under normal and severe mobile channel conditions. Under normal channel conditions, similar results have been obtained when using ARQ schemes. However, under severe mobile channel conditions, the FEC code with interleaving shows better performance.

Digital communication networks incorporating mobile data terminals

The use of digital communication systems is increasing very rapidly. This is due to lower system implementation cost compared to analogue transmission and at the same time, the ease with which several types of data sources (data, digitised speech and video, etc.) can be mixed. The emergence of packet broadcast techniques as an efficient type of multiplexing, especially with the use of contention random multiple access protocols, has led to a wide-spread application of these distributed access protocols in local area networks (LANs) and a further extension of them to radio and mobile radio communication applications. In this research, a proposal for a modified version of the distributed access contention protocol which uses the packet broadcast switching technique has been achieved. The carrier sense multiple access with collision avoidance (CSMA/CA) is found to be the most appropriate protocol which has the ability to satisfy equally the operational requirements for local area networks as well as for radio and mobile radio applications. The suggested version of the protocol is designed in a way in which all desirable features of its precedents is maintained. However, all the shortcomings are eliminated and additional features have been added to strengthen its ability to work with radio and mobile radio channels. Operational performance evaluation of the protocol has been carried out for the two types of non-persistent and slotted non-persistent, through mathematical and simulation modelling of the protocol. The results obtained from the two modelling procedures validate the accuracy of both methods, which compares favourably with its precedent protocol CSMA/CD (with collision detection). A further extension of the protocol operation has been suggested to operate with multichannel systems. Two multichannel systems based on the CSMA/CA protocol for medium access are therefore proposed. These are; the dynamic multichannel system, which is based on two types of channel selection, the random choice (RC) and the idle choice (IC), and the sequential multichannel system. The latter has been proposed in order to supress the effect of the hidden terminal, which always represents a major problem with the usage of the contention random multiple access protocols with radio and mobile radio channels. Verification of their operation performance evaluation has been carried out using mathematical modelling for the dynamic system. However, simulation modelling has been chosen for the sequential system. Both systems are found to improve system operation and fault tolerance when compared to single channel operation.

The impact of the introduction of visual display terminals on the job characteristics, job satisfaction and well-being of users in government offices

The proliferation of visual display terminals (VDTs) in offices is an international phenomenon. Numerous studies have investigated the health implications which can be categorised into visual problems, symptoms of musculo-skelctal discomfort, or psychosocial effects. The psychosocial effects are broader and there is mixed evidence in this area. The inconsistent results from the studies of VDT work so far undertaken may reflect several methodological shortcomings. In an attempt to overcome these deficiencies and to broaden the model of inter-relationships a model was developed to investigate their interactions and Ihc outputs of job satisfaction, stress and ill health. The study was a two-stage, long-term investigation with measures taken before the VDTs were introduced and the same measures taken 12 months after the 'go-live' date. The research was conducted in four offices of the Department of Social Security. The data were analysed for each individual site and in addition the total data were used in a path analysis model. Significant positive relationships were found at the pre-implementation stage between the musculo-skeletal discomfort, psychosomatic ailments, visual complaints and stress. Job satisfaction was negatively related to visual complaints and musculo-skeletal discomfort. Direct paths were found for age and job level with variety found in the job and age with job satisfaction and a negative relationship with the office environment. The only job characteristic which had a direct path to stress was 'dealing with others'. Similar inter-relationships were found in the post-implementation data. However, in addition attributes of the computer system, such as screen brightness and glare, were related positively with stress and negatively with job satisfaction. The comparison of the data at the two stages found that there had been no significant changes in the users' perceptions of their job characteristics and job satisfaction but there was a small and significant reduction in the stress measure.

Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex

Presynaptic NMDA receptors facilitate the release of glutamate at excitatory cortical synapses and are involved in regulation of synaptic dynamics and plasticity. At synapses in the entorhinal cortex these receptors are tonically activated and provide a positive feedback modulation of the level of background excitation. NMDA receptor activation requires obligatory occupation of a co-agonist binding site, and in the present investigation we have examined whether this site on the presynaptic receptor is activated by endogenous glycine or d-serine. We used whole-cell patch clamp recordings of spontaneous AMPA receptor-mediated synaptic currents from rat entorhinal cortex neurones in vitro as a monitor of presynaptic glutamate release. Addition of exogenous glycine or d-serine had minimal effects on spontaneous release, suggesting that the co-agonist site was endogenously activated and likely to be saturated in our slices. This was supported by the observation that a co-agonist site antagonist reduced the frequency of spontaneous currents. Depletion of endogenous glycine by enzymatic breakdown with a bacterial glycine oxidase had little effect on glutamate release, whereas d-serine depletion with a yeast d-amino acid oxidase significantly reduced glutamate release, suggesting that d-serine is the endogenous agonist. Finally, the effects of d-serine depletion were mimicked by compromising astroglial cell function, and this was rescued by exogenous d-serine, indicating that astroglial cells are the provider of the d-serine that tonically activates the presynaptic NMDA receptor. We discuss the significance of these observations for the aetiology of epilepsy and possible targeting of the presynaptic NMDA receptor in anticonvulsant therapy. © 2014 Elsevier Ltd. All rights reserved.

Differential control of two forms of glutamate release by group III metabotropic glutamate receptors at rat entorhinal synapses

Neurotransmitter release at CNS synapses occurs via both action potential-dependent and independent mechanisms, and it has generally been accepted that these two forms of release are regulated in parallel. We examined the effects of activation of group III metabotropic glutamate receptors (mGluRs) on stimulus-evoked and spontaneous glutamate release onto entorhinal cortical neurones in rats, and found a differential regulation of action potential-dependent and independent forms of release. Activation of presynaptic mGluRs depressed the amplitude of stimulus-evoked excitatory postsynaptic currents, but concurrently enhanced the frequency of spontaneous excitatory currents. Moreover, these differential effects on glutamate release were mediated by pharmacologically separable mechanisms. Application of the specific activator of adenylyl cyclase, forskolin, mimicked the effect of mGluR activation on spontaneous, but not evoked release, and inhibition of adenylyl cyclase with 9-tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536) blocked mGluR-mediated enhancement of spontaneous release, but not depression of evoked release. Occlusion studies with calcium channel blockers suggested that the group III mGluRs might depress evoked release through inhibition of both N and P/Q, but not R-type calcium channels. We suggest that the concurrent depression of action potential-evoked, and enhancement of action potential-independent glutamate release operate through discrete second messenger/effector systems at excitatory entorhinal terminals in rat brain. © 2007 IBRO.

Astrocytes target presynaptic NMDA receptors to give synapses a boost

Astrocytes modulate synaptic strength. This effect occurs, reports a new paper, because ATP-dependent vesicular release of astrocytic glutamate acts on presynaptic neuronal NMDA receptors to increase synaptic efficacy. © 2007 Nature Publishing Group.

A simulation analysis of spoke-terminals operating in LTL Hub-and-Spoke freight distribution systems

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT The research presented in this thesis is concerned with Discrete-Event Simulation (DES) modelling as a method to facilitate logistical policy development within the UK Less-than-Truckload (LTL) freight distribution sector which has been typified by “Pallet Networks” operating on a hub-and-spoke philosophy. Current literature relating to LTL hub-and-spoke and cross-dock freight distribution systems traditionally examines a variety of network and hub design configurations. Each is consistent with classical notions of creating process efficiency, improving productivity, reducing costs and generally creating economies of scale through notions of bulk optimisation. Whilst there is a growing abundance of papers discussing both the network design and hub operational components mentioned above, there is a shortcoming in the overall analysis when it comes to discussing the “spoke-terminal” of hub-and-spoke freight distribution systems and their capabilities for handling the diverse and discrete customer profiles of freight that multi-user LTL hub-and-spoke networks typically handle over the “last-mile” of the delivery, in particular, a mix of retail and non-retail customers. A simulation study is undertaken to investigate the impact on operational performance when the current combined spoke-terminal delivery tours are separated by ‘profile-type’ (i.e. retail or nonretail). The results indicate that a potential improvement in delivery performance can be made by separating retail and non-retail delivery runs at the spoke-terminal and that dedicated retail and non-retail delivery tours could be adopted in order to improve customer delivery requirements and adapt hub-deployed policies. The study also leverages key operator experiences to highlight the main practical implementation challenges when integrating the observed simulation results into the real-world. The study concludes that DES be harnessed as an enabling device to develop a ‘guide policy’. This policy needs to be flexible and should be applied in stages, taking into account the growing retail-exposure.

The distribution of senile plaques, neurofibrillary tangles and beta/A4 deposits in the hippocampus in Alzheimer's disease

The density of senile plaques (SP) and neurofibrillary tangles (NFT) was studied in Glees and Marsland stained sections of the hippocampus and parahippocampal gyrus (PHG) in 20 pateints with Alzheimer's disease. In addition, in six of the patients, the density of beta/A4 protein deposits, as revealed by immunohistochemistry and neurofibrillary changes demonstrated with the Gallyas stain, were studied in adjacent sections. The density of Glees SP and beta/A4 deposits was significantly greater in area CA1 of the hippocampus and in the subiculum than in the PHG. Hence, neurofibrillary degeneration appears to be a more important lesion than beta/A4 deposition in the hippocampus compared with the PHG. In addition, the detailed distribution of the lesions in the hippocampus could be explained if beta/A4/SP and NFT occur on the axon terminals and in the cell bodies respectively of the same neurons.

Advanced handover procedure for cellular communication systems

Third Generation cellular communication systems are expected to support mixed cell architecture in which picocells, microcells and macrocells are used to achieve full coverage and increase the spectral capacity. Supporting higher numbers of mobile terminals and the use of smaller cells will result in an increase in the number of handovers, and consequently an increase in the time delays required to perform these handovers. Higher time delays will generate call interruptions and forced terminations, particularly for time sensitive applications like real-time multimedia and data services. Currently in the Global System for Mobile communications (GSM), the handover procedure is initiated and performed by the fixed part of the Public Land Mobile Network (PLMN). The mobile terminal is only capable of detecting candidate base stations suitable for the handover; it is the role of the network to interrogate a candidate base station for a free channel. Handover signalling is exchanged via the fixed network and the time delay required to perform the handover is greatly affected by the levels of teletraffic handled by the network. In this thesis, a new handover strategy is developed to reduce the total time delay for handovers in a microcellular system. The handover signalling is diverted from the fixed network to the air interface to prevent extra delays due to teletraffic congestion, and to allow the mobile terminal to exchange signalling directly with the candidate base station. The new strategy utilises Packet Reservation Multiple Access (PRMA) technique as a mechanism to transfer the control of the handover procedure from the fixed network to the mobile terminal. Simulation results are presented to show a dramatic reduction in the handover delay as compared to those obtained using fixed channel allocation and dynamic channel allocation schemes.

All optical networking beyond 10 Gbits/s OTDM networks based on electro-optic modulators and fibre ring lasers

This thesis examines options for high capacity all optical networks. Specifically optical time division multiplexed (OTDM) networks based on electro-optic modulators are investigated experimentally, whilst comparisons with alternative approaches are carried out. It is intended that the thesis will form the basis of comparison between optical time division multiplexed networks and the more mature approach of wavelength division multiplexed networks. Following an introduction to optical networking concepts, the required component technologies are discussed. In particular various optical pulse sources are described with the demanding restrictions of optical multiplexing in mind. This is followed by a discussion of the construction of multiplexers and demultiplexers, including favoured techniques for high speed clock recovery. Theoretical treatments of the performance of Mach Zehnder and electroabsorption modulators support the design criteria that are established for the construction of simple optical time division multiplexed systems. Having established appropriate end terminals for an optical network, the thesis examines transmission issues associated with high speed RZ data signals. Propagation of RZ signals over both installed (standard fibre) and newly commissioned fibre routes are considered in turn. In the case of standard fibre systems, the use of dispersion compensation is summarised, and the application of mid span spectral inversion experimentally investigated. For green field sites, soliton like propagation of high speed data signals is demonstrated. In this case the particular restrictions of high speed soliton systems are discussed and experimentally investigated, namely the increasing impact of timing jitter and the downward pressure on repeater spacings due to the constraint of the average soliton model. These issues are each addressed through investigations of active soliton control for OTDM systems and through investigations of novel fibre types respectively. Finally the particularly remarkable networking potential of optical time division multiplexed systems is established, and infinite node cascadability using soliton control is demonstrated. A final comparison of the various technologies for optical multiplexing is presented in the conclusions, where the relative merits of the technologies for optical networking emerges as the key differentiator between technologies.