Recent evidence indicates that long-chain polyunsaturated fatty acids (PUFAs) can prevent cardiac arrhythmias by a reduction of cardiomyocyte excitability. This was shown to be due to a modulation of the voltage-dependent inactivation of both sodium (INa) and calcium (ICa) currents. To establish whether PUFAs also regulate neuronal excitability, the effects of PUFAs on INa and ICa were assessed in CAl neurons freshly isolated from the rat hippocampus. Extracellular application of PUFAs produced a concentrationdependent shift of the voltage dependence of inactivation of both INa and ICa to more hyperpolarized potentials. Consequently, they accelerated the inactivation and retarded the recovery from inactivation. The EC50 for the shift of the INa steady-state inactivation curve was 2.1 + 0.4 ,uM for docosahexaenoic acid (DHA) and 4 + 0.4 ,uM for eicosapentaenoic acid (EPA). The EC50 for the shift on the ICa inactivation curve was 2.1 + 0.4 for DHA and >15 ,uM for EPA. Additionally, DHA
To explore non-synaptic mechanisms in paroxysmal discharges, we used a computer model of a simplified hippocampal pyramidal cell, surrounded by interstitial space and a "glial-endothelial" buffer system. Ion channels for Na+, K+, Ca2+ and Cl- ion antiport 3Na/Ca, and "active" ion pumps were represented in the neuron membrane. The glia had "leak" conductances and an ion pump. Fluxes, concentration changes and cell swelling were computed. The neuron was stimulated by injecting current. Afterdischarge (AD) followed stimulation if depolarization due to rising interstitial K+ concentration ([K+]o) activated persistent Na+ current (INa.P). AD was either simple or self-regenerating; either regular (tonic) or burst-type (clonic); and always self-limiting. Self-regenerating AD required sufficient INa.P to ensure re-excitation. Burst firing depended on activation of dendritic Ca2+ currents and Ca-dependent K+ current. Varying glial buffer function influenced [K+]o accumulation and afterdischarge duration. Variations in Na+ and K+ currents influenced the threshold and the duration of AD. The data show that high [K+]o and intrinsic membrane currents can produce the feedback of self-regenerating afterdischarges without synaptic input. The simulated discharge resembles neuron behavior during paroxysmal firing in living brain tissue.
Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat Faas, G.C.; Vreugdenhil, M.; Wadman, W.J. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Abstract--Calcium is an important second messenger which plays a role in the regulation of neuronal excitability and in many forms of synaptic plasticity. In kindling epileptogenesis, a model of focal epilepsy, calcium plays an important role. The in situ patch-clamp technique was used to record calcium currents in slices obtained from kindled rats and controls. We found that low-voltage-activated calcium currents, probably of dendritic origin, were larger after kindling (80%). The transient high-voltage-activated calcium currents were also enhanced after kindling (50% higher). The increase of the current is accompanied by a decrease in the time constant of inactivation. The change was still present six weeks after the kindling stimulations were stopped. These data demonstrate that low-voltage-activated calcium currents are involved in epileptogenesis. Their enhancement in the dendrites will boost synaptic depolarization and result in enhanced calcium influx, which is critically dependent on the specific activation pattern.
In this computational study, we investigated (i) the functional importance of correlated basal ganglia (BG) activity associated with Parkinson's disease (PD) motor symptoms by analysing the effects of globus pallidus internum (GPi) bursting frequency and synchrony on a thalamocortical (TC) relay neuron, which received GABAergic projections from this nucleus; (ii) the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on the response of the TC relay neuron to synchronized GPi oscillations; and (iii) the functional basis of the inverse relationship that has been reported between DBS frequency and stimulus amplitude, required to alleviate PD motor symptoms [A. L. Benabid et al. (1991)Lancet, 337, 403-406]. The TC relay neuron selectively responded to and relayed synchronized GPi inputs bursting at a frequency located in the range 2-25 Hz. Input selectivity of the TC relay neuron is dictated by low-threshold calcium current dynamics and passive membrane properties of the neuron. STN-DBS prevented the TC relay neuron from relaying synchronized GPi oscillations to cortex. Our model indicates that DBS alters BG output and input selectivity of the TC relay neuron, providing an explanation for the clinically observed inverse relationship between DBS frequency and stimulus amplitude.
Schizophrenia has been associated with a dysfunction of brain dopamine (DA). This, so called, DA hypothesis has been refined as new insights into the pathophysiology of schizophrenia have emerged. Currently, dysfunction of prefrontocortical glutamatergic and GABAergic projections and dysfunction of serotonin (5-HT) systems are also thought to play a role in the pathophysiology of schizophrenia. Refinements of the DA hypothesis have lead to the emergence of new pharmacological targets for antipsychotic drug development. It was shown that effective antipsychotic drugs with a low liability for inducing extra-pyramidal side-effects have affinities for a range of neurotransmitter receptors in addition to DA receptors, suggesting that a combination of neurotransmitter receptor affinities may be favorable for treatment outcome.This review focuses on the interaction between DA and 5-HT, as most antipsychotics display affinity for 5-HT receptors. We will discuss DA/5-HT interactions at the level of receptors and G protein-coupled potassium channels and consequences for induction of depolarization blockade with specific attention to DA neurons in the ventral tegmental area (VTA) and the substantia nigra zona compacta (SN), neurons implicated in treatment efficacy and the side-effects of schizophrenia, respectively. Moreover, it has been reported that electrophysiological interactions between DA and 5-HT show subtle, but important, differences between the SN and the VTA which could explain (in part) the effectiveness and lower propensity to induce side-effects of the newer atypical antipsychotic drugs. In that respect the functional implications of DA/5-HT interactions for schizophrenia will be discussed.Key Words: Schizophrenia, antipsychotic drug, substantia nigra, ventral tegmental area. DOPAMINE AND SCHIZOPHRENIAThe mesocortical pathway, the mesolimbic pathway, the nigrostriatal pathway and the tuberoinfundibular pathway have all been postulated to be involved in the pathophysiology of schizophrenia and the propensity of antipsychotic drugs to induce side-effects [144]. Hypofunction of the mesocortical pathway and hyperfunction of the mesolimbic pathway [44,55,144] are thought to be responsible for the symptoms that can be observed (see also Sesack and Carr, 2002 [138])) and points to one of the many difficulties for effective treatment: increasing dopamine (DA) activity in the mesocortical pathway, while concomitantly decreasing DA activity in the mesolimbic pathway. The nigrostriatal and tuberoinfundibular pathways are involved in side-effects of antipsychotic drug treatment, such as extra-pyramidal side effects and hyperprolactinemia, respectively [10, 30] which are related to changes in firing activity of neurons in these pathways, especially the DA neurons. What lies at the root of this mesocortical mesolimbic dysfunction is unclear but loss of cholinergic interneurons in the striatum, hypoglutamatergia or "miswiring" of glutamatergic and _-amino butyric acid (GABA)-ergic projections from the prefrontal...
As described by others, an extracellular calciumsensitive non-selective cation channel ([Ca 2+ ] o -sensitive NSCC) of central neurons opens when extracellular calcium level decreases. An other non-selective current is activated by rising intracellular calcium ([Ca 2+ ] i ). The [Ca 2+ ] osensitive NSCC is not dependent on voltage and while it is permeable by monovalent cations, it is blocked by divalent cations. We tested the hypothesis that activation of this channel can promote seizures and spreading depression (SD). We used a computer model of a neuron surrounded by interstitial space and enveloped in a glia-endothelial "buffer" system. Na + , K + , Ca 2+ and Cl − concentrations, ion fluxes and osmotically driven volume changes were computed. Conventional ion channels and the NSCC were incorporated in the neuron membrane. Activation of NSCC conductance caused the appearance of paroxysmal afterdischarges (ADs) at parameter settings that did not produce AD in the absence of NSCC. The duration of the AD depended on the amplitude of the NSCC. Similarly, NSCC also enabled the generation of SD. We conclude that NSCC can contribute to the generation of epileptiform events and to spreading depression. (Caeser et al. 1993;Crepel et al. 1994) and substantia nigra inhibitory neurons (Lee and Tepper 2007). The TRPM4b channel, which is expressed in mammalian neurons, has been characterized as a [Ca 2+ ] i -activated, Ca 2+ -impermeable, monovalent cation-permeable channel (Fleig and Penner 2004;Launay et al. 2002). Since uptake of Ca 2+ into neurons results simultaneously in an increase in [Ca 2+ ] i and a decrease in [Ca 2+ ] o , if the two Ca 2+ sensitive currents co-exist in the same cell, they are expected to reinforce one another and in fact could perhaps be generated by the same channel (see Section 3).
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