Biology subjects

Deller, T.

Publications and source records attributed to Deller, T..

10 recordsLinked to original sources

bioRxiv2025

ATXN2 polyglutamine expansion impairs QKI-dependent alternative splicing and oligodendrocyte maintenance

BackgroundPolyglutamine (polyQ) tract expansion mutations in Ataxin-2 gene (ATXN2) are associated with neurodegenerative diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS), while the therapeutic reduction of ATXN2 confers strong health-/lifespan extension in models of both disorders. Although the involvement of ATXN2 in peripheral lipid metabolism has been elaborated in Atxn2 knock-out mice, its impact on nervous system lipid maintenance and a potential influence on oligodendrocytes remains unexplored. MethodsWe examine the nervous tissue of an authentic ATXN2 polyQ expansion mouse model in terms of (i) gross morphology of the brain and differential glial affection via immunohistochemical analyses, (ii) spinocerebellar proteome profile via label-free mass spectroscopy and (iii) alternative splicing patterns of oligodendroglial transcripts via quantitative RT-PCR. Finally, electrophysiological recording of sensory response in cerebellar Purkinje cells was performed as a phenotypic measure of demyelination. ResultsWe demonstrate a massive impairment in myelin maintenance due to ATXN2 polyQ expansion, affecting key oligodendroglial proteins accompanied by their splicing anomalies much earlier than disease manifestation. Oligodendroglial ATXN2 aggregates were documented for the first time in cerebellum, which sequestrated the RNA splicing factor Quaking (QKI). As an outcome of demyelination, our SCA2 model showed a significant delay in response to sensory stimuli. ConclusionsOverall, we provide pioneer evidence of oligodendroglial proteotoxicity leading to myelin maintenance defects in an authentic mouse model of SCA2. Our findings suggest that not only neuronal metabolism, but also that of oligodendroglia depends on ATXN2 and is affected during the disease course. This novel aspect of ATXN2 pathomechanism sheds light on potential outcomes of its therapeutic manipulation, and makes it relevant also for demyelination syndromes next to SCA2 and other polyQ disorders.

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bioRxiv2023

Skewed distribution of spines is independent of presynaptic transmitter release and synaptic plasticity and emerges early during adult neurogenesis

Dendritic spines are crucial for excitatory synaptic transmission as the size of a spine head correlates with the strength of its synapse. The distribution of spine head sizes follows a lognormal-like distribution with more small spines than large ones. We analysed the impact of synaptic activity and plasticity on the spine size distribution in adult-born hippocampal granule cells from rats with induced homo- and heterosynaptic long-term plasticity in vivo and CA1 pyramidal cells from Munc-13-1-Munc13-2 knockout mice with completely blocked synaptic transmission. Neither induction of extrinsic synaptic plasticity nor the blockage of presynaptic activity degrades the lognormal-like distribution but changes its mean, variance and skewness. The skewed distribution develops early in the life of the neuron. Our findings and their computational modelling support the idea that intrinsic synaptic plasticity is sufficient for the generation, while a combination of intrinsic and extrinsic synaptic plasticity maintains lognormal like distribution of spines.

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bioRxiv2022

The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

The perforant path provides the main cortical excitatory input to the hippocampus. Due to its important role in information processing and coding, entorhinal projections to the dentate gyrus have been studied in considerable detail. Nevertheless, a characterization of synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells is still pending. Here, we have used organotypic entorhino-hippocampal tissue cultures, in which the entorhino-dentate (EC-GC) projection is present and EC-GC pairs can be studied using whole-cell patch clamp recordings. Using cultures of wildtype mice, the properties of EC-GC synapses formed by afferents from the lateral and medial entorhinal cortex were compared and differences in short-term plasticity were revealed. Since the perforant path is severely affected in Alzheimers disease, we used cultures of APP-deficient mice to address the role of the amyloid-precursor protein (APP) at this synapse. APP-deficiency caused alterations in excitatory neurotransmission at medial perforant path synapses that were accompanied by transcriptomic and ultrastructural changes. Moreover, the deletion of pre- but not postsynaptic APP through the local injection of Cre-expressing AAVs in conditional APPflox/flox tissue cultures increased the efficacy of neurotransmission at perforant path synapses. Together, these data suggest a physiological role for presynaptic APP at medial perforant path synapses, which may be adversely affected under conditions of altered APP processing.

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bioRxiv2021

All-trans retinoic acid induces synaptopodin-dependent metaplasticity in mouse dentate granule cells

The vitamin A derivative all-trans retinoic acid (atRA) is a key mediator of synaptic plasticity. Depending on the brain region studied, distinct effects of atRA on excitatory and inhibitory neurotransmission have been reported. However, it remains unclear how atRA mediates brain region-specific effects on synaptic transmission and plasticity. Here, we used intraperitoneal injections of atRA (10 mg/kg) in adult male C57BL/6J mice to study the effects of atRA on excitatory and inhibitory neurotransmission in the mouse fascia dentata. In contrast to what has been reported in other brain regions, no major changes in synaptic transmission were observed in the ventral and dorsal hippocampus 6 hours after atRA administration. Likewise, no evidence for changes in the intrinsic properties of hippocampal dentate granule cells was obtained in the atRA-treated group. Moreover, hippocampal transcriptome analysis revealed no essential changes upon atRA treatment. In light of these findings, we tested for the metaplastic effects of atRA, i.e., for its ability to modulate synaptic plasticity expression in the absence of major changes in baseline synaptic transmission. Indeed, in vivo long-term potentiation (LTP) experiments demonstrated that systemic atRA treatment improves the ability of dentate granule cells to express LTP. The plasticity-promoting effects of atRA were not observed in synaptopodin-deficient mice, thus extending our previous results on the relevance of synaptopodin in atRA-mediated synaptic strengthening in the mouse prefrontal cortex. Taken together, our data show that atRA mediates synaptopodin-dependent metaplasticity in mouse dentate granule cells.

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bioRxiv2020

Neural inflammation alters synaptic plasticity probed by 10 Hz repetitive magnetic stimulation

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNF) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNF, IL6, IL1{beta}, and IFN{gamma} and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.

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bioRxiv2020

All-Trans Retinoic Acid induces synaptic plasticity in human cortical neurons

A defining feature of the brain is its ability to adapt structural and functional properties of synaptic contacts in an experience-dependent manner. In the human cortex direct experimental evidence for synaptic plasticity is currently missing. Here, we probed plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid, which has been suggested as medication for the treatment of neuropsychiatric disorders, e.g., Alzheimers disease. Our experiments demonstrate coordinated structural and functional changes of excitatory synapses of superficial (layer 2/3) pyramidal neurons in the presence of all-trans retinoic acid. This synaptic adaptation is accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and requires mRNA-translation. We conclude that all-trans retinoic acid is a potent mediator of synaptic plasticity in the adult human cortex.

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bioRxiv2020

Amyloid-beta mediates homeostatic synaptic plasticity

The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPs in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures of APP-/- mice. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-{beta} (A{beta}) and not by APPs, and it is neither observed in APP+/+ tissue treated with {beta}- or {gamma}-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increased A{beta} levels.

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bioRxiv2020

The actin-modulating protein Synaptopodin mediates long-term survival of dendritic spines

Large spines are stable and important for memory trace formation. The majority of large spines also contains Synaptopodin (SP), an actin-modulating and plasticity-related protein. Since SP stabilizes F-actin, we speculated that the presence of SP within large spines could explain their long lifetime. Indeed, using time-lapse 2-photon-imaging of SP-transgenic granule cells in mouse organotypic tissue cultures we found that spines containing SP survived considerably longer than spines of equal size without SP. Of note, SP-positive spines that underwent pruning first lost SP before disappearing. Whereas the survival time courses of SP-positive (SP+) spines followed conditional two-phase decay functions, SP-negative (SP-) spines and all spines of SP-deficient animals showed single exponential decays. These results implicate SP as a major regulator of long-term spine stability: SP clusters stabilize spines and the presence of SP indicates spines of high stability.

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bioRxiv2019

A general principle of dendritic constancy – a neuron’s size and shape invariant excitability

Reducing neuronal size results in less cell membrane and therefore lower input conductance. Smaller neurons are thus more excitable as seen in their voltage responses to current injections in the soma. However, the impact of a neurons size and shape on its voltage responses to synaptic activation in dendrites is much less understood. Here we use analytical cable theory to predict voltage responses to distributed synaptic inputs and show that these are entirely independent of dendritic length. For a given synaptic density, a neurons response depends only on the average dendritic diameter and its intrinsic conductivity. These results remain true for the entire range of possible dendritic morphologies irrespective of any particular arborisation complexity. Also, spiking models result in morphology invariant numbers of action potentials that encode the percentage of active synapses. Interestingly, in contrast to spike rate, spike times do depend on dendrite morphology. In summary, a neurons excitability in response to synaptic inputs is not affected by total dendrite length. It rather provides a homeostatic input-output relation that specialised synapse distributions, local non-linearities in the dendrites and synaptic plasticity can modulate. Our work reveals a new fundamental principle of dendritic constancy that has consequences for the overall computation in neural circuits.\n\nIn briefWe show that realistic neuron models essentially collapse to point neurons when stimulated by randomly distributed inputs instead of by single synapses or current injection in the soma.\n\nHighlightsO_LIA simple equation that predicts voltage in response to distributed synaptic inputs.\nC_LIO_LIResponses to distributed and clustered inputs are largely independent of dendritic length.\nC_LIO_LISpike rates in various Hodgkin Huxley (HH) like or Leaky Integrate-and-Fire (LIF) models are largely independent of morphology.\nC_LIO_LIPrecise spike timing (firing pattern) depends on dendritic morphology.\nC_LIO_LINeuroMorpho.Org database-wide analysis of the relation between dendritic morphology and electrophysiology.\nC_LIO_LIOur equations set precise input-output relations in realistic dendrite models.\nC_LI

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bioRxiv2019

Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.

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