Biomedical subjects

Knut Holthoff

Publications and source records attributed to Knut Holthoff.

10 recordsLinked to original sources

PubMed2006

Nuclear calcium signals during L-LTP induction do not predict the degree of synaptic potentiation.

The magnitude and/or duration of nuclear Ca(2+)-transients has been shown to dose-dependently modulate gene transcription upon neuronal activation. This is an attractive model for synapse-to-nucleus communication. In order to encode synaptic information, these nuclear Ca(2+)-transients have to be correlated with changes in synaptic strength rather than changes in gene expression patterns. In this study, we analysed nuclear Ca(2+) signals during L-LTP induction. Using a combined approach of fEPSP recordings and two-photon imaging, these Ca(2+) signals were correlated with different degrees of synaptic potentiation in CA1 hippocampal slices. To refine our analysis on the single-cell level, we developed a new approach called single-cell-excitability-probing (SCEP) to assay the plasticity outcome of individual cells by optical means. The degrees of synaptic potentiation we observed could be categorized into transcription independent, transcription-dependent and reduced transcription-dependent. There is no consistent dose-dependent relationship between these different degrees of synaptic potentiation and the magnitude, the decay time and the area under the curve of nuclear Ca(2+)-transients during L-LTP induction. This indicates that nuclear Ca(2+)-transients during induction are unsuited to grade the degree of plasticity in an analogue manner. We propose a role for nuclear Ca(2+) as a digital on/off switch for activating transcription.

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PubMed2006

Dendritic spikes and activity-dependent synaptic plasticity.

Whereas the regenerative nature of action potential conduction in axons has been known since the late 1940s, neuronal dendrites have been considered as passive cables transferring incoming synaptic activity to the soma. The relatively recent discovery that neuronal dendrites contain active conductances has revolutionized our view of information processing in neurons. In many neuronal cell types, sodium action potentials initiated at the axon initial segment can back-propagate actively into the dendrite thereby serving, for the dendrite, as an indicator of the output activity of the neuron. In addition, the dendrites themselves can initiate action-potential-like regenerative responses, so-called dendritic spikes, that are mediated either by the activation of sodium, calcium, and/or N-methyl-D-aspartate receptor channels. Here, we review the recent experimental and theoretical evidence for a role of regenerative dendritic activity in information processing within neurons and, especially, in activity-dependent synaptic plasticity.

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PubMed2004

Single-shock LTD by local dendritic spikes in pyramidal neurons of mouse visual cortex.

Mammalian dendrites are active structures, capable of regenerative electrical activity. Dendritic spikes can mediate synaptic plasticity and could enrich the computational properties of neurons. Besides sodium-based action potentials, which can propagate throughout the dendritic tree, neocortical pyramidal neurons also sustain dendritic spikes that are spatially restricted. The function of these 'local' dendritic spikes is unknown. We show that local spikes, which require activation of N-methyl-d-aspartate receptors (NMDARs), induce long-term synaptic depression (LTD) in layer 5 pyramidal neurons. This depression does not require somatic spiking and is input specific. Moreover, a single synaptic stimulus can evoke a dendritic spike and a brief local dendritic calcium transient, and is sufficient for the full induction of LTD.

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PubMed2004

Neurotrophin action on a rapid timescale.

Mechanisms underlying the fast action of neurotrophins include intracellular Ca(2+) signaling, neuronal excitation, augmentation of synaptic excitation by modulation of N-methyl-d-aspartate receptor activity and control of synaptic inhibition through the regulation of the K(+)-Cl(-) cotransporter KCC2. The fastest action of brain-derived neurotrophic factor and neurotrophin-4/5 occurs within milliseconds, and involves activation of TrkB and the opening of the Na(+) channel Na(v)1.9. Through these rapid actions, neurotrophins shape neuronal activity, modulate synaptic transmission and produce instructive signals for the induction of long-term changes in the efficacy of synaptic transmission.

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PubMed2004

Regenerative dendritic spikes and synaptic plasticity.

During the last decade, our vision of the neuronal dendritic tree has changed from a simple input device conducting afferent input as a passive cable to the cell soma to a series of independent and actively operating processing units. Different voltage- and ligand-gated ion channels located in the dendritic tree not only participate in processing afferent inputs but also enable the dendritic tree to initiate regenerative spikes, traditionally considered to be exclusively restricted to axonal structures. Recent results suggest that these local dendritic spikes may act as a means to initiate long-term synaptic plasticity. Different from Hebbian synaptic plasticity this type of induction does not need axonal action potential firing and backpropagation into the dendrite. This new proximity learning rule, first postulated by neural network theorists, may have large significance for the information processing in the brain.

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PubMed2003

In vivo two-photon calcium imaging of neuronal networks.

Two-photon calcium imaging is a powerful means for monitoring the activity of distinct neurons in brain tissue in vivo. In the mammalian brain, such imaging studies have been restricted largely to calcium recordings from neurons that were individually dye-loaded through microelectrodes. Previous attempts to use membrane-permeant forms of fluorometric calcium indicators to load populations of neurons have yielded satisfactory results only in cell cultures or in slices of immature brain tissue. Here we introduce a versatile approach for loading membrane-permeant fluorescent indicator dyes in large populations of cells. We established a pressure ejection-based local dye delivery protocol that can be used for a large spectrum of membrane-permeant indicator dyes, including calcium green-1 acetoxymethyl (AM) ester, Fura-2 AM, Fluo-4 AM, and Indo-1 AM. We applied this dye-loading protocol successfully in mouse brain tissue at any developmental stage from newborn to adult in vivo and in vitro. In vivo two-photon Ca2+ recordings, obtained by imaging through the intact skull, indicated that whisker deflection-evoked Ca2+ transients occur in a subset of layer 2/3 neurons of the barrel cortex. Thus, our results demonstrate the suitability of this technique for real-time analyses of intact neuronal circuits with the resolution of individual cells.

Animals↗

PubMed2003

Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.

Hyperpolarization-activated cation (HCN) channels are believed to be involved in the generation of cardiac pacemaker depolarizations as well as in the control of neuronal excitability and plasticity. The contributions of the four individual HCN channel isoforms (HCN1-4) to these diverse functions are not known. Here we show that HCN2-deficient mice exhibit spontaneous absence seizures. The thalamocortical relay neurons of these mice displayed a near complete loss of the HCN current, resulting in a pronounced hyperpolarizing shift of the resting membrane potential, an altered response to depolarizing inputs and an increased susceptibility for oscillations. HCN2-null mice also displayed cardiac sinus dysrhythmia, a reduction of the sinoatrial HCN current and a shift of the maximum diastolic potential to hyperpolarized values. Mice with cardiomyocyte- specific deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results define the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity.

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PubMed2002

Calcium dynamics of spines depend on their dendritic location.

Dendritic spines are morphologically and functionally heterogeneous. To understand this diversity, we use two-photon imaging of layer 5 neocortical pyramidal cells and measure action potential-evoked [Ca(2+)]i transients in spines. Spine calcium kinetics are controlled by (i) the diameter of the parent dendrite, (ii) the length of the spine neck, and (iii) the strength of spine calcium pumps. These factors produce different calcium dynamics in spines from basal, proximal apical, and distal apical dendrites, differences that are more pronounced without exogenous buffers. In proximal and distal apical dendrites, different calcium dynamics correlate with different susceptibility to synaptic depression, and modifying calcium kinetics in spines changes the expression of long-term depression. Thus, the spine location apparently determines its calcium dynamics and synaptic plasticity. Our results highlight the precision in design of neocortical neurons.

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PubMed2002

A problem with Hebb and local spikes.

Although our understanding of the cellular properties of mammalian neurons is increasing rapidly, the computational function of their elaborate dendritic trees is still mysterious. In recent years, experiments have shown that, in pyramidal cells, individual dendritic compartments sustain local excitation spikes.. These dendrites also support Hebbian synaptic plasticity, which depends on the precise temporal relationship between pre- and postsynaptic spikes. In this review we discuss what we consider to be a problem with Hebbian (i.e., spike-timing-dependent) plasticity. We argue that most of the spikes that occur in dendrites are not back-propagating action potentials but but local spikes, and that Hebbian plasticity caused by local spikes can undermine the functional integrity of the geometrically complex dendritic tree. We propose that the inverted Hebbian plasticity of synapses involved in local spikes, and/or local dendritic homeostatic plasticity, could prevent an unbalanced distribution of synaptic weights on the dendritic tree.

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PubMed2002

Calcium dynamics in spines: link to synaptic plasticity.

Dendritic spines are morphologically and functionally heterogeneous. Here, we use two-photon imaging of layer V pyramidal neurons in slices from mouse visual cortex to characterize differences in spine calcium dynamics between individual spines. By measuring action potential-evoked [Cell transients in spines, we find different calcium dynamics in spines from proximal apical and distal apical dendrites. Using a mathematical multi-compartmental model, we demonstrate that these differences are even more pronounced in the absence of exogenous calcium buffers. We also find that these different calcium dynamics cause different susceptibility to synaptic depression in proximal and distal apical synapses, and that modifying calcium decay kinetics in spines changes the expression of long-term depression. We conclude that the location of the spine determines its time window of calcium compartmentalization and degree of calcium-dependent synaptic plasty. Our results highlight the precision of the design of neocortical neurons.

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