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Biomedical subjects

Tobias Bonhoeffer

Publications and source records attributed to Tobias Bonhoeffer.

At least 19 recordsLinked to original sources
PubMed2006

A balance of protein synthesis and proteasome-dependent degradation determines the maintenance of LTP.

Long-lasting changes in synaptic strength are thought to play a pivotal role in activity-dependent plasticity and memory. There is ample evidence indicating that in hippocampal long-term potentiation (LTP) the synthesis of new proteins is crucial for enduring changes. However, whether protein degradation also plays a role in this process has only recently begun to receive attention. Here, we examine the effects of blocking protein degradation on LTP. We show that pharmacological inhibition of proteasome-dependent protein degradation, just like inhibition of protein synthesis, disrupts expression of late (L-)LTP. However, when protein degradation and protein synthesis are inhibited at the same time, LTP is restored to control levels, calling into question the commonly held hypothesis that synthesis of new proteins is indispensable for L-LTP. Instead, these findings point to a more facetted model, in which L-LTP is determined by the combined action of synthesis and degradation of plasticity proteins.

Amino Acids↗
PubMed2006

Highly ordered arrangement of single neurons in orientation pinwheels.

In the visual cortex of higher mammals, neurons are arranged across the cortical surface in an orderly map of preferred stimulus orientations. This map contains 'orientation pinwheels', structures that are arranged like the spokes of a wheel such that orientation changes continuously around a centre. Conventional optical imaging first demonstrated these pinwheels, but the technique lacked the spatial resolution to determine the response properties and arrangement of cells near pinwheel centres. Electrophysiological recordings later demonstrated sharply selective neurons near pinwheel centres, but it remained unclear whether they were arranged randomly or in an orderly fashion. Here we use two-photon calcium imaging in vivo to determine the microstructure of pinwheel centres in cat visual cortex with single-cell resolution. We find that pinwheel centres are highly ordered: neurons selective to different orientations are clearly segregated even in the very centre. Thus, pinwheel centres truly represent singularities in the cortical map. This highly ordered arrangement at the level of single cells suggests great precision in the development of cortical circuits underlying orientation selectivity.

Animals↗
PubMed2006

Lifelong learning: ocular dominance plasticity in mouse visual cortex.

Ocular dominance plasticity has long served as a successful model for examining how cortical circuits are shaped by experience. In this paradigm, altered retinal activity caused by unilateral eye-lid closure leads to dramatic shifts in the binocular response properties of neurons in the visual cortex. Much of the recent progress in identifying the cellular and molecular mechanisms underlying ocular dominance plasticity has been achieved by using the mouse as a model system. In this species, monocular deprivation initiated in adulthood also causes robust ocular dominance shifts. Research on ocular dominance plasticity in the mouse is starting to provide insight into which factors mediate and influence cortical plasticity in juvenile and adult animals.

Animals↗
PubMed2006

Homeostatic shutdown of long-term potentiation in the adult hippocampus.

Homeostasis is a key concept in biology. It enables ecosystems, organisms, organs, and cells to adjust their operating range to values that ensure optimal performance. Homeostatic regulation of the strength of neuronal connections has been shown to play an important role in the development of the nervous system. Here we investigate whether mature neurons also possess mechanisms to prevent the strengthening of input synapses once the limit of their operating range has been reached. Using electrophysiological recordings in hippocampal slices, we show that such a mechanism exists but comes into play only after a considerable number of synapses have been potentiated. Thus, adult neurons can sustain a substantial amount of synaptic strengthening but, once a certain threshold of potentiation is exceeded, homeostatic regulation ensures that no further strengthening can occur.

Aging↗
PubMed2006

Hippocampal long-term potentiation is supported by presynaptic and postsynaptic tyrosine receptor kinase B-mediated phospholipase Cgamma signaling.

Neurotrophins have been shown to play a critical role in activity-dependent synaptic plasticity such as long-term potentiation (LTP) in the hippocampus. Although the role of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor [tyrosine receptor kinase B (TrkB)] is well documented, it still remains unresolved whether presynaptic or postsynaptic activation of TrkB is involved in the induction of LTP. To address this question, we locally and specifically interfered with a downstream target of the TrkB receptor, phospholipase Cgamma (PLCgamma). We prevented PLCgamma signaling by overexpression of the PLCgamma pleckstrin homology (PH) domain with a Sindbis virus vector. The isolated PH domain has an inhibitory effect and thereby blocks endogenous PLCgamma signaling and consequently also IP3 production. Surprisingly, concurrent presynaptic and postsynaptic blockade of PLCgamma signaling was required to reduce LTP to levels comparable with those in TrkB and BDNF knock-out mice. Blockade of presynaptic or postsynaptic signaling alone did not result in a significant reduction of LTP.

Animals↗
PubMed2006

Neuronal activity determines the protein synthesis dependence of long-term potentiation.

Long-term potentiation (LTP) is generally divided into two phases, early (E-) and late (L-) LTP, of which only L-LTP is thought to depend on protein synthesis. Here we report that E-LTP can also be dependent on protein synthesis at higher levels of synaptic activation. Moreover, we show that the requirement for protein synthesis during L-LTP extends beyond the early induction phase and that it depends on synaptic stimulation. This suggests that the level of neuronal activity is a crucial determinant for the role of protein synthesis in E- and L-LTP.

Animals↗
PubMed2005

Prior experience enhances plasticity in adult visual cortex.

The brain has a remarkable capacity to adapt to alterations in its sensory environment, which is normally much more pronounced in juvenile animals. Here we show that in adult mice, the ability to adapt to changes can be improved profoundly if the mouse has already experienced a similar change in its sensory environment earlier in life. Using the standard model for sensory plasticity in mouse visual cortex-ocular dominance (OD) plasticity-we found that a transient shift in OD, induced by monocular deprivation (MD) earlier in life, renders the adult visual cortex highly susceptible to subsequent MD many weeks later. Irrespective of whether the first MD was experienced during the critical period (around postnatal day 28) or in adulthood, OD shifts induced by a second MD were faster, more persistent and specific to repeated deprivation of the same eye. The capacity for plasticity in the mammalian cortex can therefore be conditioned by past experience.

Aging↗
PubMed2005

The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons.

The correlation between functional and structural neuronal plasticity is by now well documented. However, the molecular mechanisms translating patterns of neuronal activity into specific changes in the structure of neurons remain unclear. Neurotrophins can be released in an activity-dependent manner, and they are capable of controlling both neuronal morphology and functional synaptic changes. They are thus attractive molecules to be studied in the context of synaptic plasticity. In the CNS, most of the work so far has focused on the role of BDNF and of its tyrosine kinase B receptor (TrkB), but relatively little is known about the function of the pan-neurotrophin receptor p75NTR. In this study, we show in loss-of-function experiments that postnatal hippocampal pyramidal cells in two mutant lines of p75NTR have a higher spine density and greater dendritic complexity than wild-type (WT) mice. Conversely, in a gain-of-function approach, p75NTR overexpression in WT neurons significantly reduces dendritic complexity, as well as spine density in all dendritic compartments. These results show that p75NTR negatively modulates dendritic morphology in adult hippocampal pyramidal neurons and documents a new case of functional antagonism between Trk and p75NTR signaling.

Animals↗
PubMed2005

Altered map of visual space in the superior colliculus of mice lacking early retinal waves.

During the development of the mammalian retinocollicular projection, a coarse retinotopic map is set up by the graded distribution of axon guidance molecules. Subsequent refinement of the initially diffuse projection has been shown to depend on the spatially correlated firing of retinal ganglion cells. In this scheme, the abolition of patterned retinal activity is not expected to influence overall retinotopic organization, but this has not been investigated. We used optical imaging of intrinsic signals to visualize the complete retinotopic map in the superior colliculus (SC) of mice lacking early retinal waves, caused by the deletion of the beta2 subunit of the nicotinic acetylcholine receptor. As expected from previous anatomical studies in the SC of beta2(-/-) mice, regions activated by individual visual stimuli were much larger and had less sharp borders than those in wild-type mice. Importantly, however, we also found systematic distortions of the entire retinotopic map: the map of visual space was expanded anteriorly and compressed posteriorly. Thus, patterned neuronal activity in the early retina has a substantial influence on the coarse retinotopic organization of the SC.

Animals↗
PubMed2005

Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion.

We tracked pathogenic myelin basic protein-specific CD4+ effector T cells in early central nervous system (CNS) lesions of experimental autoimmune encephalomyelitis (EAE) by combining two-photon imaging and fluorescence video microscopy. We made two key observations: (a) the majority of the cells (65%) moved fast (maximal speed 25 microm/min) and apparently nondirected through the compact tissue; and (b) a second group of effector T cells (35%) appeared tethered to a fixed point. Polarization of T cell receptor and adhesion molecules (lymphocyte function-associated antigen 1) towards this fixed point suggests the formation of immune synapses. Nonpathogenic, ovalbumin-specific T cells were not tethered in the CNS and did not form synapse-like contacts, but moved through the tissue. After intrathecal injection of antigen, 40% of ovalbumin-specific T cells became tethered. Conversely, injection of anti-major histocompatibility complex class II antibodies profoundly reduced the number of stationary pathogenic T cells within the CNS (to 15%). We propose that rapid penetration of the CNS parenchyma by numerous autoimmune effector T cells along with multiple autoantigen-presentation events are responsible for the fulminate development of clinical EAE.

Animals↗
PubMed2005

The neurotrophin receptor p75NTR modulates long-term depression and regulates the expression of AMPA receptor subunits in the hippocampus.

Neurotrophins are involved in the modulation of synaptic transmission, including the induction of long-term potentiation (LTP) through the receptor TrkB. Because previous studies have revealed a bidirectional mode of neurotrophin action by virtue of signaling through either the neurotrophin receptor p75NTR or the Trk receptors, we tested the hypothesis that p75NTR is important for longterm depression (LTD) to occur. Although LTP was found to be unaffected in hippocampal slices of two different strains of mice carrying mutations of the p75NTR gene, hippocampal LTD was impaired in both p75NTR-deficient mouse strains. Furthermore, the expression levels of two (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits, GluR2 and GluR3, but not GluR1 or GluR4, were found to be significantly altered in the hippocampus of p75NTR-deficient mice. These results implicate p75NTR in activity-dependent synaptic plasticity and extend the concept of functional antagonism of the neurotrophin signaling system.

Animals↗
PubMed2005

Visual cortex: two-photon excitement.

Current in vivo methods for imaging the visual cortex lack the ability to map response properties at the level of single cells. A new technique using two-photon imaging of calcium signals has now overcome this limitation.

Animals↗
PubMed2005

Local calcium transients regulate the spontaneous motility of dendritic filopodia.

During development, dendrites, and in particular dendritic filopodia, undergo extensive structural remodeling, presumably to help establish synaptic contacts. Here, we investigated the role of calcium signaling in dendritic plasticity by simultaneously recording calcium dynamics and filopodial growth in rat hippocampal slice cultures. Local calcium transients occurred in dendritic filopodia and shafts, often at putative synaptic sites. These events were highly correlated with filopodial motility: comparatively rare when individual filopodia emerged from the dendrite, they became more frequent after filopodia started growing, finally causing them to halt. Accordingly, an experimental reduction of the frequency of local calcium transients elicited filopodial growth and, conversely, calcium uncaging reduced filopodial motility. Our observations suggest that low levels of local calcium transients facilitate filopodial outgrowth, whereas high levels inhibit the formation of filopodia and stabilize newly formed ones. This process may facilitate synapse formation and may serve as a homeostatic mechanism distributing synapses evenly along developing dendrites.

2-Amino-5-phosphonovalerate↗
PubMed2004

Competing for memory: hippocampal LTP under regimes of reduced protein synthesis.

The persistence of synaptic potentiation in the hippocampus is known to depend on transcription and protein synthesis. We report here that, under regimes of reduced protein synthesis, competition between synapses for the relevant intracellular proteins can be demonstrated. Under such circumstances, the induction of additional protein synthesis-dependent long-term potentiation for a given set of postsynaptic neurons occurs at the expense of the maintenance of prior potentiation on an independent pathway. This new phenomenon, which we call "competitive maintenance," has important functional consequences, and it may be explained in terms of dynamic interactions between synapses and "plasticity factors" over extended periods of time.

Animals↗
PubMed2004

Bidirectional activity-dependent morphological plasticity in hippocampal neurons.

Dendritic spines on pyramidal neurons receive the vast majority of excitatory input and are considered electrobiochemical processing units, integrating and compartmentalizing synaptic input. Following synaptic plasticity, spines can undergo morphological plasticity, which possibly forms the structural basis for long-term changes in neuronal circuitry. Here, we demonstrate that spines on CA1 pyramidal neurons from organotypic slice cultures show bidirectional activity-dependent morphological plasticity. Using two-photon time-lapse microscopy, we observed that low-frequency stimulation induced NMDA receptor-dependent spine retractions, whereas theta burst stimulation led to the formation of new spines. Moreover, without stimulation the number of spine retractions was on the same order of magnitude as the stimulus-induced spine gain or loss. Finally, we found that the ability of neurons to eliminate spines in an activity-dependent manner decreased with developmental age. Taken together, our data show that hippocampal neurons can undergo bidirectional morphological plasticity; spines are formed and eliminated in an activity-dependent way.

Animals↗
PubMed2004

High-resolution functional optical imaging: from the neocortex to the eye.

Much work remains to be done to establish the clinical usefulness of the RFI for early diagnosis and treatment guidance. The discoveries obtained by functional optical imaging of the neocortex in the last 15 years and the recent RFI studies of the eyes of normal subjects and patients with diabetic retinopathy, glaucoma, and age-related macular degeneration suggest that functional optical imaging of the retina is likely to become a multi-modality powerful clinical tool.

Animals↗
PubMed2003

Hippocampal plasticity requires postsynaptic ephrinBs.

Chemical synapses contain specialized pre- and postsynaptic structures that regulate synaptic transmission and plasticity. EphB receptor tyrosine kinases are important molecular components in this process. Previously, EphB receptors were shown to act postsynaptically, whereas their transmembrane ligands, the ephrinBs, were presumed to act presynaptically. Here we show that in mouse hippocampal CA1 neurons, the Eph/ephrin system is used in an inverted manner: ephrinBs are predominantly localized postsynaptically and are required for synaptic plasticity. We further demonstrate that EphA4, a candidate receptor, is also critically involved in long-term plasticity independent of its cytoplasmic domain, suggesting that ephrinBs are the active signaling partner. This work raises the intriguing possibility that depending on the type of synapse, Eph/ephrins can be involved in activity-dependent plasticity in converse ways, with ephrinBs on the pre- or the postsynaptic side.

Animals↗