Publications by authors named "Blanka Kellermayer"

7 Publications

  • Page 1 of 1

Distance-dependent regulation of NMDAR nanoscale organization along hippocampal neuron dendrites.

Proc Natl Acad Sci U S A 2020 09 14;117(39):24526-24533. Epub 2020 Sep 14.

Interdisciplinary Institute for Neuroscience, University of Bordeaux, UMR 5297, 33076 Bordeaux, France;

Hippocampal pyramidal neurons are characterized by a unique arborization subdivided in segregated dendritic domains receiving distinct excitatory synaptic inputs with specific properties and plasticity rules that shape their respective contributions to synaptic integration and action potential firing. Although the basal regulation and plastic range of proximal and distal synapses are known to be different, the composition and nanoscale organization of key synaptic proteins at these inputs remains largely elusive. Here we used superresolution imaging and single nanoparticle tracking in rat hippocampal neurons to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDA receptors (NMDARs)-which play key roles in the use-dependent adaptation of glutamatergic synapses-along the dendritic arbor. We report significant changes in the nanoscale organization of GluN2B-NMDARs between proximal and distal dendritic segments, whereas the topography of GluN2A-NMDARs remains similar along the dendritic tree. Remarkably, the nanoscale organization of GluN2B-NMDARs at proximal segments depends on their interaction with calcium/calmodulin-dependent protein kinase II (CaMKII), which is not the case at distal segments. Collectively, our data reveal that the nanoscale organization of NMDARs changes along dendritic segments in a subtype-specific manner and is shaped by the interplay with CaMKII at proximal dendritic segments, shedding light on our understanding of the functional diversity of hippocampal glutamatergic synapses.
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http://dx.doi.org/10.1073/pnas.1922477117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533699PMC
September 2020

Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease.

Cell Rep 2019 06;27(13):3860-3872.e4

Interdisciplinary Institute for NeuroSciences, CNRS UMR 5297, 33077 Bordeaux, France; Université de Bordeaux, 33077 Bordeaux, France. Electronic address:

Astrocytes constantly adapt their ramified morphology in order to support brain cell assemblies. Such plasticity is partly mediated by ion and water fluxes, which rely on the water channel aquaporin-4 (AQP4). The mechanism by which this channel locally contributes to process dynamics has remained elusive. Using a combination of single-molecule and calcium imaging approaches, we here investigated in hippocampal astrocytes the dynamic distribution of the AQP4 isoforms M1 and M23. Surface AQP4-M1 formed small aggregates that contrast with the large AQP4-M23 clusters that are enriched near glutamatergic synapses. Strikingly, stabilizing surface AQP4-M23 tuned the motility of astrocyte processes and favors glutamate synapse activity. Furthermore, human autoantibodies directed against AQP4 from neuromyelitis optica (NMO) patients impaired AQP4-M23 dynamic distribution and, consequently, astrocyte process and synaptic activity. Collectively, it emerges that the membrane dynamics of AQP4 isoform regulate brain cell assemblies in health and autoimmune brain disease targeting AQP4.
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http://dx.doi.org/10.1016/j.celrep.2019.05.097DOI Listing
June 2019

Differential Nanoscale Topography and Functional Role of GluN2-NMDA Receptor Subtypes at Glutamatergic Synapses.

Neuron 2018 10 27;100(1):106-119.e7. Epub 2018 Sep 27.

Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France; CNRS, IINS UMR 5297, Bordeaux, France. Electronic address:

NMDA receptors (NMDARs) play key roles in the use-dependent adaptation of glutamatergic synapses underpinning memory formation. In the forebrain, these plastic processes involve the varied contributions of GluN2A- and GluN2B-containing NMDARs that have different signaling properties. Although the molecular machinery of synaptic NMDAR trafficking has been under scrutiny, the postsynaptic spatial organization of these two receptor subtypes has remained elusive. Here, we used super-resolution imaging of NMDARs in rat hippocampal synapses to unveil the nanoscale topography of native GluN2A- and GluN2B-NMDARs. Both subtypes were found to be organized in separate nanodomains that vary over the course of development. Furthermore, GluN2A- and GluN2B-NMDAR nanoscale organizations relied on distinct regulatory mechanisms. Strikingly, the selective rearrangement of GluN2A- and GluN2B-NMDARs, with no overall change in NMDAR current amplitude, allowed bi-directional tuning of synaptic LTP. Thus, GluN2A- and GluN2B-NMDAR nanoscale organizations are differentially regulated and seem to involve distinct signaling complexes during synaptic adaptation.
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http://dx.doi.org/10.1016/j.neuron.2018.09.012DOI Listing
October 2018

Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients.

Nat Commun 2017 11 27;8(1):1791. Epub 2017 Nov 27.

Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, 33077, Bordeaux, France.

The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients' NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.
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http://dx.doi.org/10.1038/s41467-017-01700-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702610PMC
November 2017

Differential role of the proteasome in the early and late phases of BDNF-induced facilitation of LTP.

J Neurosci 2015 Feb;35(8):3319-29

Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal, and

The neurotrophin brain-derived neurotrophic factor (BDNF) mediates activity-dependent long-term changes of synaptic strength in the CNS. The effects of BDNF are partly mediated by stimulation of local translation, with consequent alterations in the synaptic proteome. The ubiquitin-proteasome system (UPS) also plays an important role in protein homeostasis at the synapse by regulating synaptic activity. However, whether BDNF acts on the UPS to mediate the effects on long-term synaptic potentiation (LTP) has not been investigated. In the present study, we show similar and nonadditive effects of BDNF and proteasome inhibition on the early phase of synaptic potentiation (E-LTP) induced by theta-burst stimulation of rat hippocampal CA1 synapses. The effects of BDNF were blocked by the proteasome activator IU1, suggesting that the neurotrophin acts by decreasing proteasome activity. Accordingly, BDNF downregulated the proteasome activity in cultured hippocampal neurons and in hippocampal synaptoneurosomes. Furthermore, BDNF increased the activity of the deubiquitinating enzyme UchL1 in synaptoneurosomes and upregulated free ubiquitin. In contrast to the effects on posttetanic potentiation, proteasome activity was required for BDNF-mediated LTP. These results show a novel role for BDNF in UPS regulation at the synapse, which is likely to act together with the increased translation activity in the regulation of the synaptic proteome during E-LTP.
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http://dx.doi.org/10.1523/JNEUROSCI.4521-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605551PMC
February 2015

Ordered subset analysis of copy number variation association with age at onset of Alzheimer's disease.

J Alzheimers Dis 2014 ;41(4):1063-71

Department of Bioinformatics, University at Buffalo, SUNY, Buffalo, NY, USA.

Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer's disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor that facilitates amyloid-β1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets.
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http://dx.doi.org/10.3233/JAD-132693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866488PMC
March 2015

Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase.

Hum Immunol 2013 Dec 7;74(12):1701-4. Epub 2013 Aug 7.

Division of Clinical and Experimental Neuroimmunology, Department of Neurology, University of Pecs, Pecs, Hungary.

Introduction: Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders.

Methods: The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls.

Results: The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01).

Discussion: The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found.
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http://dx.doi.org/10.1016/j.humimm.2013.07.016DOI Listing
December 2013