Biomedical subjects

Andreas Draguhn

Publications and source records attributed to Andreas Draguhn.

12 recordsLinked to original sources

PubMed2005

Induced sharp wave-ripple complexes in the absence of synaptic inhibition in mouse hippocampal slices.

The characteristic, behaviour-related network oscillations of the mammalian hippocampus (, gamma and ripples) are accompanied by strongly phase-coupled action potentials in specific subsets of GABAergic interneurones. It has been suggested that the resulting phasic, repetitive inhibition shapes rhythmic coherent activity of the neuronal network. Here, we examined whether synaptic inhibition entrains approximately 200 Hz network ripples by applying the GABA(A) receptor antagonist gabazine to CA1 minislices of mouse hippocampus. Gabazine blocked spontaneously occurring sharp wave-ripple (SPW-R) activity. However, local application of KCl to the dendritic layer elicited excitatory sharp waves on which approximately 200 Hz ripple oscillations were superimposed with equal temporal properties of native SPW-R. The activity also persisted in the additional presence of blockers of glutamatergic synaptic transmission. In contrast, synchrony was largely abolished after addition of gap junction blockers. Thus, GABAergic transmission appears to be involved in the generation of sharp waves but phasic inhibition is no prerequisite for the precise synchronization of hippocampal neurones during high-frequency oscillations at approximately 200 Hz. Gap junctions on the other hand seem to be necessary to orchestrate coordinated activity within the ripple frequency domain.

Action Potentials↗

PubMed2004

Ionotropic GABA receptors with mixed pharmacological properties of GABAA and GABAC receptors.

Ionotropic gamma-aminobutyric acid (GABA) receptors form a large family of molecular isoforms with distinct properties. We have characterized a distinct new type of GABA receptors in CA1 pyramidal cells in rat hippocampal slices. Somatic application of GABA induced currents which were partially suppressed by (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), a specific antagonist of GABA(C) receptors. This sensitivity was enhanced when we evoked the currents by the GABA(C) receptor agonist cis-4-aminocrotonic acid (CACA). However, both GABA- and CACA-evoked currents were sensitive towards bicuculline and thus lack the defining feature of GABA(C) receptors, which are insensitive towards this antagonist. Spontaneous miniature post-synaptic currents (mIPSCs) revealed a similar pharmacological behaviour. We conclude that juvenile CA1 pyramidal cells express a fraction of ionotropic GABA receptors with mixed pharmacological properties of both, GABA(A) and GABA(C) receptors.

Animals↗

PubMed2004

Neuronal oscillations in cortical networks.

Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain's design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.

Animals↗

PubMed2004

Inhibition of GABA release by presynaptic ionotropic GABA receptors in hippocampal CA3.

Vesicular transmitter release can be regulated by transmitter-gated ion channels at presynaptic axon terminals. The central inhibitory transmitter GABA acts on such presynaptic ionotropic receptors in various cells, including inhibitory interneurons. Here we report that GABA-mediated postsynaptic inhibitory currents in CA3 pyramidal cells of rat hippocampal slices are suppressed by agonists of GABAA receptors. The effect is present for both stimulus-induced and miniature IPSCs, indicating a reduction in the probability of vesicular release by presynaptic, action-potential-independent mechanisms. We conclude that the release of GABA from hippocampal CA3 interneurons is regulated by a negative feedback via presynaptic ionotropic GABA autoreceptors.

Animals↗

PubMed2004

Two-photon imaging of spontaneous vesicular release in acute brain slices and its modulation by presynaptic GABAA receptors.

Action potential-independent spontaneous vesicular release of gamma-aminobutyric acid (GABA) in the CNS mediates miniature inhibitory postsynaptic currents (mIPSCs) and exerts an important control on central excitability. Using dual-photon laser scan microscopy and hyperosmotic loading of the readily releasable vesicle pool with the fluorescent styryl dye FM1-43 in hippocampal slice, we demonstrate action potential-independent release of vesicles (fluorescence destaining) from proximal perisomatic, presumed GABAergic terminals and significant inhibition of this release by the specific GABA(A) receptor agonist muscimol in the presence of tetrodotoxin and glutamate receptor antagonists CNQX and AP5. These data agree with reduction of mIPSCs by muscimol in whole-cell recordings from CA3 pyramidal neurons. In contrast, rate of vesicle release from distal, presumably glutamatergic terminals, was significantly lower and not changed by muscimol. The effect of muscimol on mIPSCs was not blocked but rather enhanced in the absence of external calcium. Our data directly demonstrate a potent disinhibitory reduction of GABA release by GABA(A) receptor activation. Those novel methods should be well suited to study pathophysiological changes in inhibition in resections obtained from neurosurgical treatment of epilepsy patients.

Animals↗

PubMed2003

Transmitter metabolism as a mechanism of synaptic plasticity: a modeling study.

The nervous system adapts to experience by changes in synaptic strength. The mechanisms of synaptic plasticity include changes in the probability of transmitter release and in postsynaptic responsiveness. Experimental and neuropharmacological evidence points toward a third variable in synaptic efficacy: changes in presynaptic transmitter concentration. Several groups, including our own, have reported changes in the amplitude and frequency of postsynaptic (miniature) events indicating that alterations in transmitter content cause alterations in vesicular transmitter content and vesicle dynamics. It is, however, not a priori clear how transmitter metabolism will affect vesicular transmitter content and how this in turn will affect pre- and postsynaptic functions. We therefore have constructed a model of the presynaptic terminal incorporating vesicular transmitter loading and the presynaptic vesicle cycle. We hypothesize that the experimentally observed synaptic plasticity after changes in transmitter metabolism puts predictable restrictions on vesicle loading, cytoplasmic-vesicular transmitter concentration gradient, and on vesicular cycling or release. The results of our model depend on the specific mechanism linking presynaptic transmitter concentration to vesicular dynamics, that is, alteration of vesicle maturation or alteration of release. It also makes a difference whether differentially filled vesicles are detected and differentially processed within the terminal or whether vesicle filling acts back onto the terminal by presynaptic autoreceptors. Therefore, the model allows one to decide, at a given synapse, how transmitter metabolism is linked to presynaptic function and efficacy.

Animals↗

PubMed2003

Cellular and network mechanisms underlying spontaneous sharp wave-ripple complexes in mouse hippocampal slices.

The mammalian hippocampus displays a peculiar pattern of fast (approximately 200 Hz) network oscillations superimposed on slower sharp waves. Such sharp wave-ripple complexes (SPW-R) have been implicated in memory consolidation. We have recently described a novel and unique method for studying SPW-R in naive slices of murine hippocampus. Here, we used this model to analyse network and cellular mechanisms of this type of network activity. SPW-R are usually generated within area CA3 but can also originate within the isolated CA1 region. Cellular synchronisation during SPW-R requires both excitatory and inhibitory synaptic transmission as well as electrical coupling, the latter being particularly important for the high-frequency component. Extracellular and intracellular recordings revealed a surprisingly strong inhibition of most CA1 pyramidal cells during SPW-R. A minority of active cells, however, increases action potential frequency and fires in strict synchrony with the field ripples. This strong separation between members and non-members of the network may serve to ensure a high signal-to-noise ratio in information processing during sharp wave-ripple complexes.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Unaltered control of extracellular GABA-concentration through GAT-1 in the hippocampus of rats after pilocarpine-induced status epilepticus.

The uptake of the inhibitory transmitter GABA (gamma-aminobutyric acid) limits the efficacy of synaptic and tonic inhibition in brain tissue. It has been reported that GABA-uptake is down-regulated in temporal lobe epilepsy. This down-regulation may increase the inhibitory action of GABA but may also limit the anticonvulsant activity of GABA-uptake blockers. We have directly compared the function of GABA-uptake in hippocampal slices from normal and chronically epileptic rats. We raised the global extracellular concentration of GABA by bath-application of the agonist in the absence and presence of the GABA-uptake blocker tiagabine. GABA-induced currents were measured in dentate granule cells and CA1 pyramidal neurons in hippocampal slices. The potentiation of currents by tiagabine was taken as a measure for the efficacy of GABA-uptake in the hippocampal tissue. There was no difference between cells from control- or pilocarpine-treated animals in the response to GABA or in the conductance increase following application of tiagabine. Our data show that in the chronic phase of the pilocarpine-model GABA-uptake maintains its ability to control the extracellular background concentration of GABA.

Animals↗

PubMed2002

Reduction of high-frequency network oscillations (ripples) and pathological network discharges in hippocampal slices from connexin 36-deficient mice.

Recent evidence suggests that electrotonic coupling is an important mechanism for neuronal synchronisation in the mammalian cortex and hippocampus. Various types of network oscillations have been shown to depend on, or be sharpened by, gap junctions between inhibitory interneurones or excitatory projection cells. Here we made use of a targeted disruption of the gene coding for Cx36, a recently discovered neuronal gap junction subunit, to analyse its role in hippocampal network behaviour. Mice lacking Cx36 are viable and lack obvious morphological or behavioural abnormalities. Stimulation of afferent and efferent fibre pathways in hippocampal slices revealed a largely normal function of the synaptic circuitry, including tetanically evoked network oscillations. Spontaneous sharp waves and ripple (approximately 200 Hz) oscillations, however, occurred less frequently in slices from Cx36 -/- mice, and ripples were slightly slower than in littermate controls. Moreover, epileptiform discharges elicited by 4-aminopyridine were attenuated in slices from Cx36 -/- mice. Our findings indicate that Cx36 plays a role in the generation of certain forms of network synchronisation in the hippocampus, namely sharp wave-ripple complexes and hypersynchronous epileptiform discharges.

4-Aminopyridine↗

PubMed2002

Glutamate-induced gamma oscillations in the dentate gyrus of rat hippocampal slices.

In this paper we show that gamma oscillations can be elicited by brief (< or = 200 ms) local applications of glutamate in the dentate gyrus of rat hippocampal slices. Dentate gamma oscillations show an initial peak frequency of approximately 70 Hz and last for up to 4 min. The network activity involves functional GABA(A) receptors as it is drastically reduced by GABA(A) receptor antagonists. The oscillations can be observed in the whole dentate gyrus-CA3-network and are coherent between the dentate gyrus and area CA3 for variable periods. Thus, long-lasting gamma oscillations can be experimentally induced in the dentate gyrus and are propagated into the hippocampus proper.

Animals↗

PubMed2002

Axonal gap junctions between principal neurons: a novel source of network oscillations, and perhaps epileptogenesis.

We hypothesized in 1998 that gap junctions might be located between the axons of principal hippocampal neurons, based on the shape of spikelets (fast prepotentials), occurring during gap junction-mediated very fast (to approximately 200 Hz) network oscillations in vitro. More recent electrophysiological, pharmacological and dye-coupling data indicate that axonal gap junctions exist; so far, they appear to be located about 100 microm from the soma, in CA1 pyramidal neurons. Computer modeling and theory predict that axonal gap junctions can lead to very fast network oscillations under three conditions: a) there are spontaneous axonal action potentials; b) the number of gap junctions in the network is neither too low (not less than to approximately 1.5 per cell on average), nor too high (not more than to approximately 3 per cell on average); c) action potentials can cross from axon to axon via gap junctions. Simulated oscillations resemble biological ones, but condition (c) remains to be demonstrated directly. Axonal network oscillations can, in turn, induce oscillatory activity in larger neuronal networks, by a variety of mechanisms. Axonal networks appear to underlie in vivo ripples (to approximately 200 Hz field potential oscillations superimposed on physiological sharp waves), to drive gamma (30-70 Hz) oscillations that appear in the presence of carbachol, and to initiate certain types of ictal discharge. If axonal gap junctions are important for seizure initiation in humans, there could be practical consequences for antiepileptic therapy: at least one gap junction-blocking compound, carbenoxolone, is already in clinical use (for treatment of ulcer disease), and it crosses the blood-brain barrier.

Animals↗

PubMedDate not supplied

Functional GABA uptake at inhibitory synapses in CA1 of chronically epileptic rats.

Inhibitory postsynaptic currents were measured in CA1 pyramidal cells from chronically epileptic rats (pilocarpine model). Tiagabine, a selective inhibitor of the GABA-uptake transporter 1 prolonged currents equally to cells from control animals. Thus, GABA-uptake has an unaltered impact on inhibitory synaptic efficacy in rats with chronic temporal lobe epilepsy, underlining the rational for the use of GABA-uptake blockers in this condition.

Animals↗