Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

Sustained neuronal activity generated by glial plasticity

Astrocytes release gliotransmitters, notably glutamate, that can affect neuronal and synaptic activity. In particular, astrocytic glutamate release results in the generation of NMDA receptor (NMDA-R)-mediated slow inward currents (SICs) in neurons. However, factors underlying the emergence of SICs and their physiological roles are essentially unknown. Here we show that, in acute slices of rat somatosensory thalamus, stimulation of lemniscal or cortical afferents results in a sustained increase of SICs in thalamocortical (TC) neurons that outlasts the duration of the stimulus by 1 h. This long-term enhancement of astrocytic glutamate release is induced by group I metabotropic glutamate receptors and is dependent on astrocytic intracellular calcium. Neuronal SICs are mediated by extrasynaptic NR2B subunit-containing NMDA-Rs and are capable of eliciting bursts. These are distinct from T-type Ca2+ channel-dependent bursts of action potentials and are synchronized in neighboring TC neurons. These findings describe a previously unrecognized form of excitatory, nonsynaptic plasticity in the CNS that feeds forward to generate local neuronal firing long after stimulus termination.

An investigation into the synaptic conditions and celluar mechanisms underlying cerebellar synaptic plasticity

The direction of synaptic plasticity at the connection between parallel fibres (PFs) and Purkinje cells can be modified by PF stimulation alone. Strong activation (Hartell, 1996) or high frequency stimulation (Schreurs and Alkon, 1993) of PFs induced a long-term depression (LTD) of PF-mediated excitatory postsynaptic currents. Brief raised frequency molecular layer stimulation produced a cAMP-dependent long-temi potentiation (LTP) of field potential (FP) responses (Salin et al., 1998). Thin slices of cerebellar vermis were prepared from 14-21 day old male Wistar rats decapitated under Halothane anaesthesia. FP's were recorded from the Purkinje cell layer in response to alternate 0.2Hz activation of stimulating electrodes placed in the molecular layer. In the presence of picrotoxin, FPs displayed two tetrodotoxin-sensitive, negative-going components termed N1 and N2. EPs were graded responses with paired pulse facilitation and were selectively blocked by 101AM 6-cyano-7-nitroquinoxaline-2,3-dicne (CNQX) an antagonist at iy,-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type ionotropic glutamate receptors (AMPAR) suggesting that they were primarily PE-mediated. The effects of raised stimulus intensity (RS) and/or increased frequency (IF) activation of the molecular layer on FP responses were examined. In sagittai and transverse slices combined RS and IF molecular layer activation induced a LTD of the N2 component of FP responses. RSIF stimulation produced fewer incidences of LTD in sagittal slices when an inhibitor of nitric oxide synthase (NOS), guanylate cyclase (GC), protein kinase G (PKG) or the GABAB receptor antagonist CGP62349 was included into the perfusion medium. Application of a nitric oxide (NO) donor, a cyclic guanosine monophosphate (cGMP) analogue or a phosphodiesterase (PDE) type V inhibitor to prevent cGMP breakdown paired with IF stimulation produced an acute depression, Raised frequency (RF) molecular layer stimulation produced a slowly emerging LTD of N2 in sagittal slices that was largely blocked in the presence of NOS, cGMP or PKG inhibitors. In transverse slices RE stimulation produced a LTP of the N2 component that was prevented by an inhibitor of protein kinase A or NOS. Inhibition of cGMP-signalling frequently revealed an underlying potentiation suggesting that cGMP activity might mask the effects of cAMP. In sagittal slices RE stimulation resulted in a potentiation of FPs when the cAMP-specific PDE type IV inhibitor rolipram was incorporated into the perfusion medium. In summary, raised levels of PE stimulation can alter the synaptic efficacy at PF-Purkinje cell synapses. The results provide support for a role of NO/cGMP/PKG signalling in the induction of LTD in the cerebellar cortex and suggest that activation of GABAa receptors might also be important. The level of cyclic nucleotide-specific PDE activities may be crucial in determining the level of cGMP and CAMP activity and hence the direction of synaptic plasticity.

On the mechanisms of cerebellar synaptic plasticity

Changes in the strength of signalling between neurones are thought to provide a cellular substrate for learning and memory. In the cerebellar cortex, raising the frequency and the strength of parallel fibre (PF) stimulation leads to a long-term depression (LTD) of the strength of signalling at the synapse between PFs and Purkinje cells (PCs), which spreads to distant synapses to the same cell via a nitric oxide (NO) dependent mechanism. At the same synapse, but under conditions of reduced post-synaptic calcium activity, raised frequency stimulation (RFS) of PFs triggers a long-term potentiation of synaptic transmission. The aims of the work described in this thesis were to investigate the conditions necessary for LTD and LTP at this synapse following RFS and to identify the origins and second messenger cascades involved in the induction and spread of LTP and LTD. In thin, parasagittal cerebellar slices whole cell patch clamp recordings were made from PCs and the effects of RFS of one of two, independent PF inputs to the same PC were examined under a range of experimental conditions. Under conditions designed to reduce post-synaptic calcium activity, RFS to a single PF input led to LTP and a decreases in paired pulse facilitation (PPF) in both pathways. This heterosynaptic potentiation was prevented by inhibition of protein kinase A (PKA) or by inhibition of NO synthase with either 7-nitroindazole (7-NI) or NG Nitro-L-argenine methyl ester. Inhibition of guanylate cyclase (GC) or protein kinase G (PKG) had no effect. A similar potentiation was observed upon application of the adenylyl cyclase (AC) activator forskolin or the NO donor spermine NONOate. Both of these treatments also resulted in an increase in the frequency of mEPSCs, which provides further evidence for a presynaptic origin of LTP. Forskolin induced potentiation and the increase in mEPSC frequency were blocked by 7-NI. The styryl dye FM1-43, a fluorescent reporter of endo- and exocytosis, was also used to further examine the possible pre-synaptic origins of LTP. RFS or forskolin application enhanced FM1-43 de-staining and NOS inhibitors blocked this effect. Application of NONOate also enhanced FM1-43 de-staining. When post-synaptic calcium activity was less strictly buffered, RFS to a single PF input led to a transient potentiation that was succeeded by LTD in both pathways. This LTD, which resembled previously described forms, was prevented by inhibition of the NO/cGMP/PKG cascade. Modification of the AC/cAMP/PKA cascade had no effect. In summary, the direction of synaptic plasticity at the PF-PC synapse in response to RFS depends largely on the level of post-synaptic calcium activity. LTP and LTD were non-input specific and both forms of plasticity were dependent on NOS activity. Induction of LTP was mediated by a presynaptic mechanism and depended on NO and cAMP production. LTD on the other hand was a post-synaptic process and required activity of the NO/cGMP/PKG signalling cascade.

Plasticity, plasticity, plasticity . . . and the rigid problem of sex

Why is popular understanding of female-male differences still based on rigid models of development, even though contemporary developmental sciences emphasize plasticity? Is it because the science of sex differences still works from the same rigid models?

Astrocyte plasticity:implications for synaptic and neuronal activity

Astrocytes are increasingly implicated in a range of functions in the brain, many of which were previously ascribed to neurons. Much of the prevailing interest centers on the role of astrocytes in the modulation of synaptic transmission and their involvement in the induction of forms of plasticity such as long-term potentiation and long-term depression. However, there is also an increasing realization that astrocytes themselves can undergo plasticity. This plasticity may be manifest as changes in protein expression which may modify calcium activity within the cells, changes in morphology that affect the environment of the synapse and the extracellular space, or changes in gap junction astrocyte coupling that modify the transfer of ions and metabolites through astrocyte networks. Plasticity in the way that astrocytes release gliotransmitters can also have direct effects on synaptic activity and neuronal excitability. Astrocyte plasticity can potentially have profound effects on neuronal network activity and be recruited in pathological conditions. An emerging principle of astrocyte plasticity is that it is often induced by neuronal activity, reinforcing our emerging understanding of the working brain as a constant interaction between neurons and glial cells. © The Author(s) 2013.

Power industry restructuring and eco-efficiency changes:a new slacks-based model in Malmquist-Luenberger Index measurement

Measuring variations in efficiency and its extension, eco-efficiency, during a restructuring period in different industries has always been a point of interest for regulators and policy makers. This paper assesses the impacts of restructuring of procurement in the Iranian power industry on the performance of power plants. We introduce a new slacks-based model for Malmquist-Luenberger (ML) Index measurement and apply it to the power plants to calculate the efficiency, eco-efficiency, and technological changes over the 8-year period (2003-2010) of restructuring in the power industry. The results reveal that although the restructuring had different effects on the individual power plants, the overall growth in the eco-efficiency of the sector was mainly due to advances in pure technology. We also assess the correlation between efficiency and eco-efficiency of the power plants, which indicates a close relationship between these two steps, thus lending support to the incorporation of environmental factors in efficiency analysis. © 2014 Elsevier Ltd.

Cost-effective and eco-friendly synthesis of novel and stable N-doped ZnO/g-C3N4 core-shell nanoplates with excellent visible-light responsive photocatalysis

N-doped ZnO/g-C3N4 hybrid core–shell nanoplates have been successfully prepared via a facile, cost-effective and eco-friendly ultrasonic dispersion method for the first time. HRTEM studies confirm the formation of the N-doped ZnO/g-C3N4 hybrid core–shell nanoplates with an average diameter of 50 nm and the g-C3N4 shell thickness can be tuned by varying the content of loaded g-C3N4. The direct contact of the N-doped ZnO surface and g-C3N4 shell without any adhesive interlayer introduced a new carbon energy level in the N-doped ZnO band gap and thereby effectively lowered the band gap energy. Consequently, the as-prepared hybrid core–shell nanoplates showed a greatly enhanced visible-light photocatalysis for the degradation of Rhodamine B compare to that of pure N-doped ZnO surface and g-C3N4. Based on the experimental results, a proposed mechanism for the N-doped ZnO/g-C3N4 photocatalyst was discussed. Interestingly, the hybrid core–shell nanoplates possess high photostability. The improved photocatalytic performance is due to a synergistic effect at the interface of the N-doped ZnO and g-C3N4 including large surface-exposure area, energy band structure and enhanced charge-separation properties. Significantly, the enhanced performance also demonstrates the importance of evaluating new core–shell composite photocatalysts with g-C3N4 as shell material.

Glial plasticity

Editorial

Astrocyte and neuronal plasticity in the somatosensory system

Changing the whisker complement on a rodent's snout can lead to two forms of experience-dependent plasticity (EDP) in the neurons of the barrel cortex, where whiskers are somatotopically represented. One form, termed coding plasticity, concerns changes in synaptic transmission and connectivity between neurons. This is thought to underlie learning and memory processes and so adaptation to a changing environment. The second, called homeostatic plasticity, serves to maintain a restricted dynamic range of neuronal activity thus preventing its saturation or total downregulation. Current explanatory models of cortical EDP are almost exclusively neurocentric. However, in recent years, increasing evidence has emerged on the role of astrocytes in brain function, including plasticity. Indeed, astrocytes appear as necessary partners of neurons at the core of the mechanisms of coding and homeostatic plasticity recorded in neurons. In addition to neuronal plasticity, several different forms of astrocytic plasticity have recently been discovered. They extend from changes in receptor expression and dynamic changes in morphology to alteration in gliotransmitter release. It is however unclear how astrocytic plasticity contributes to the neuronal EDP. Here, we review the known and possible roles for astrocytes in the barrel cortex, including its plasticity.

Eco-efficiency measurement and material balance principle:an application in power plants Malmquist Luenberger Index

Incorporating Material Balance Principle (MBP) in industrial and agricultural performance measurement systems with pollutant factors has been on the rise in recent years. Many conventional methods of performance measurement have proven incompatible with the material flow conditions. This study will address the issue of eco-efficiency measurement adjusted for pollution, taking into account materials flow conditions and the MBP requirements, in order to provide ‘real’ measures of performance that can serve as guides when making policies. We develop a new approach by integrating slacks-based measure to enhance the Malmquist Luenberger Index by a material balance condition that reflects the conservation of matter. This model is compared with a similar model, which incorporates MBP using the trade-off approach to measure productivity and eco-efficiency trends of power plants. Results reveal similar findings for both models substantiating robustness and applicability of the proposed model in this paper.

Compartmentalization of the MAPK scaffold protein KSR1 modulates synaptic plasticity in hippocampal neurons

ERK1/2 is required for certain forms of synaptic plasticity, including the long-term potentiation of synaptic strength. However, the molecular mechanisms regulating synaptically localized ERK1/2 signaling are poorly understood. Here, we show that the MAPK scaffold protein kinase suppressor of Ras 1 (KSR1) is directly phosphorylated by the downstream kinase ERK1/2. Quantitative Western blot analysis further demonstrates that expression of mutated, feedback-deficient KSR1 promotes sustained ERK1/2 activation in HEK293 cells in response to EGF stimulation, compared to a more transient activation in control cells expressing wild-type KSR1. Immunocytochemistry and confocal imaging of primary hippocampal neurons from newborn C57BL6 mice further show that feedback phosphorylation of KSR1 significantly reduces its localization to dendritic spines. This effect can be reversed by tetrodotoxin (1 μM) or PD184352 (2 μM) treatment, further suggesting that neuronal activity and phosphorylation by ERK1/2 lead to KSR1 removal from the postsynaptic compartment. Consequently, electrophysiological recordings in hippocampal neurons expressing wild-type or feedback-deficient KSR1 demonstrate that KSR1 feedback phosphorylation restricts the potentiation of excitatory postsynaptic currents. Our findings, therefore, suggest that feedback phosphorylation of the scaffold protein KSR1 prevents excessive ERK1/2 signaling in the postsynaptic compartment and thus contributes to maintaining physiological levels of synaptic excitability. © FASEB.

Eco-car : a perfect vehicle for technical design teaching?

Design methods and tools are generally best learned and developed experientially [1]. Finding appropriate vehicles for delivering these to students is becoming increasingly challenging, especially when considering only those that will enthuse, intrigue and inspire. This paper traces the development of different eco-car design and build projects which competed in the Shell Eco-Marathon. The cars provided opportunities for experiential learning through a formal learning cycle of CDIO (Conceive, Design, Implement, Operate) or the more traditional understand, explore, create, validate, with both teams developing a functional finished prototype. Lessons learned were applied through the design of a third and fourth eco-car using experimental techniques with bio-composites, combining the knowledge of fibre reinforced composite materials and adhesives with the plywood construction techniques of the two teams. The paper discusses the importance of applying materials and techniques to a real world problem. It will also explore how eco-car and comparing traditional materials and construction techniques with high tech composite materials is an ideal teaching, learning and assessment vehicle for technical design techniques.

Eco-efficiency considering the issue of heterogeneity among power plants

One of the main objectives in restructuring power industry is enhancing the efficiency of power facilities. However, power generation industry, which plays a key role in the power industry, has a noticeable share in emission amongst all other emission-generating sectors. In this study, we have developed some new Data Envelopment Analysis models to find efficient power plants based on less fuel consumption, combusting less polluting fuel types, and incorporating emission factors in order to measure the ecological efficiency trend. We then applied these models to measuring eco-efficiency during an eight-year period of power industry restructuring in Iran. Results reveal that there has been a significant improvement in eco-efficiency, cost efficiency and allocative efficiency of the power plants during the restructuring period. It is also shown that despite the hydro power plants look eco-efficient; the combined cycle ones have been more allocative efficient than the other power generation technologies used in Iran.

Does the MK2-dependent production of TNFα regulate mGluR-dependent synaptic plasticity?

The molecular mechanisms and signalling cascades that trigger the induction of group I metabotropic glutamate receptor (GI-mGluR)-dependent long-term depression (LTD) have been the subject of intensive investigation for nearly two decades. The generation of genetically modified animals has played a crucial role in elucidating the involvement of key molecules regulating the induction and maintenance of mGluR-LTD. In this review we will discuss the requirement of the newly discovered MAPKAPK-2 (MK2) and MAPKAPK-3 (MK3) signalling cascade in regulating GI-mGluR-LTD. Recently, it has been shown that the absence of MK2 impaired the induction of GI-mGluR-dependent LTD, an effect that is caused by reduced internalization of AMPA receptors (AMPAR). As the MK2 cascade directly regulates tumour necrosis factor alpha (TNFα) production, this review will examine the evidence that the release of TNFα acts to regulate glutamate receptor expression and therefore may play a functional role in the impairment of GI-mGluRdependent LTD and the cognitive deficits observed in MK2/3 double knockout animals. The strong links of increased TNFα production in both aging and neurodegenerative disease could implicate the action of MK2 in these processes.