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Special Issue "Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2019).

Special Issue Editors

Prof. Dr. Irmgard Tegeder
Website
Guest Editor
Pharmazentrum Frankfurt, Dept. of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor Stern Kai 7, Bd. 74, 4th Fl, 60590 Frankfurt am Main, Germany
Interests: nerve injury and neuropathic pain; pain and aging; central adaptations to chronic pain; multiple sclerosis; neuroinflammation; neuro-immunologic communication; redox signaling; nitric oxide; endocannabinoids and other lipid signaling molecules; progranulin; autophagy
Special Issues and Collections in MDPI journals
Prof. Dr. Heiko J. Luhmann
Website
Guest Editor
Institute of Physiology University Medical Center Johannes-Gutenberg University Duesbergweg 6. 55128 Mainz, Germany
Interests: whisker-to-barrel cortex functions and development; neuronal activity patterns in developing cortex; GABAergic currents; chloride transporter

Special Issue Information

Dear Colleagues,

Researchers in the neurosciences from the Rhine–Main area, in Germany, including the Universities of Mainz and Frankfurt and TU Darmstadt, the Max-Planck-Institutes for brain research and biophysics, IMB, FIAS and Ernst Strüngmann Institute have established the Rhine–Main Neuroscience Network (rmn^2) to enhance collaborative research in this field. Expertise in molecular-, cellular-, and systems neuroscience constitute the hallmark of rmn^2 (http://www.rmn2.de/).

The biennial meeting of the rmn² in Oberwesel 2018 brings together the neuroscience researchers of this area and renowned keynote speakers and particularly encourages PhD or MD students to present their projects to the neuroscience community. The topics of the meeting in 2018 were:

  • Mechanisms of pain persistence and relief
  • Gene regulatory mechanisms in brain development and function
  • The neuroscience of autism spectrum disorder
  • Synaptic plasticity and learning in neuronal networks
  • Neurophysiology of cognitive functions

The Special Issue "rmn^2—Oberwesel 2018" invites all speakers and Top 10 Poster Presenters to contribute a concise review of the talk or concise introduction into the topic of the Poster. Hence, the Special Issue shall provide a collection of the meeting's highlights.

Prof. Dr. Irmgard Tegeder
Prof. Dr. Heiko J. Luhmann
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pain
  • autism
  • neuropsychiatric diseases
  • developing cortical networks
  • synaptic plasticity
  • learning
  • cognition
  • aging
  • stem cells and neurogenesis
  • drosophila models
  • neurogenetics

Published Papers (7 papers)

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Research

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Open AccessArticle
Global Proteome of LonP1+/− Mouse Embryonal Fibroblasts Reveals Impact on Respiratory Chain, but No Interdependence between Eral1 and Mitoribosomes
Int. J. Mol. Sci. 2019, 20(18), 4523; https://doi.org/10.3390/ijms20184523 - 12 Sep 2019
Cited by 1
Abstract
Research on healthy aging shows that lifespan reductions are often caused by mitochondrial dysfunction. Thus, it is very interesting that the deletion of mitochondrial matrix peptidase LonP1 was observed to abolish embryogenesis, while deletion of the mitochondrial matrix peptidase Caseinolytic Mitochondrial Matrix Peptidase [...] Read more.
Research on healthy aging shows that lifespan reductions are often caused by mitochondrial dysfunction. Thus, it is very interesting that the deletion of mitochondrial matrix peptidase LonP1 was observed to abolish embryogenesis, while deletion of the mitochondrial matrix peptidase Caseinolytic Mitochondrial Matrix Peptidase Proteolytic Subunit (ClpP) prolonged survival. To unveil the targets of each enzyme, we documented the global proteome of LonP1+/− mouse embryonal fibroblasts (MEF), for comparison with ClpP−/− depletion. Proteomic profiles of LonP1+/− MEF generated by label-free mass spectrometry were further processed with the STRING (Search tool for the retrieval of interacting genes) webserver Heidelberg for protein interactions. ClpP was previously reported to degrade Eral1 as a chaperone involved in mitoribosome assembly, so ClpP deficiency triggers the accumulation of mitoribosomal subunits and inefficient translation. LonP1+/− MEF also showed Eral1 accumulation, but no systematic effect on mitoribosomal subunits. In contrast to ClpP−/− profiles, several components of the respiratory complex-I membrane arm, of the glutathione pathway and of lysosomes were accumulated, whereas the upregulation of numerous innate immune defense components was similar. Overall, LonP1, as opposed to ClpP, appears to have no effect on translational machinery, instead it shows enhanced respiratory dysfunction; this agrees with reports on the human CODAS syndrome (syndrome with cerebral, ocular, dental, auricular, and skeletal anomalies) caused by LonP1 mutations. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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Open AccessArticle
SerThr-PhosphoProteome of Brain from Aged PINK1-KO+A53T-SNCA Mice Reveals pT1928-MAP1B and pS3781-ANK2 Deficits, as Hub between Autophagy and Synapse Changes
Int. J. Mol. Sci. 2019, 20(13), 3284; https://doi.org/10.3390/ijms20133284 - 04 Jul 2019
Cited by 1
Abstract
Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) [...] Read more.
Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As an exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension, and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was also detected for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86, and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429, and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in Drosophila melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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Open AccessArticle
A Free-Operant Reward-Tracking Paradigm to Study Neural Mechanisms and Neurochemical Modulation of Adaptive Behavior in Rats
Int. J. Mol. Sci. 2019, 20(12), 3098; https://doi.org/10.3390/ijms20123098 - 25 Jun 2019
Abstract
The ability to respond flexibly to changing environmental circumstances is a hallmark of goal-directed behavior, and compromised flexibility is associated with a wide range of psychiatric conditions in humans, such as addiction and stress-related disorders. To identify neural circuits and transmitter systems implicated [...] Read more.
The ability to respond flexibly to changing environmental circumstances is a hallmark of goal-directed behavior, and compromised flexibility is associated with a wide range of psychiatric conditions in humans, such as addiction and stress-related disorders. To identify neural circuits and transmitter systems implicated in the provision of cognitive flexibility, suitable animal paradigms are needed. Ideally, such models should be easy to implement, allow for rapid task acquisition, provide multiple behavioral readouts, and permit combination with physiological and pharmacological testing and manipulation. Here, we describe a paradigm meeting these requirements and employ it to investigate the neural substrates and neurochemical modulation of adaptive behavior. Water-restricted rats learned to emit operant responses for positive reinforcement (water reward) within minutes in a free-operant conditioning environment. Without further training, animals were able to track changes in the reward schedule. Given prior evidence that the medial prefrontal cortex (mPFC) and the dopaminergic system are required for flexible behavior, we aimed to assess both in more detail. Silencing of mPFC compromised flexible behavior when avoidance of punishment was required. Systemic injections of the D2-receptor agonist quinpirole and the D2-receptor antagonist eticlopride had complex, differential impacts on reward seeking and adaptive behavior. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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Open AccessArticle
Proteasome and Autophagy-Mediated Impairment of Late Long-Term Potentiation (l-LTP) after Traumatic Brain Injury in the Somatosensory Cortex of Mice
Int. J. Mol. Sci. 2019, 20(12), 3048; https://doi.org/10.3390/ijms20123048 - 21 Jun 2019
Cited by 1
Abstract
Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation. The acute phase (24–48 h) after TBI is often characterized by neural dysfunction in the vicinity of the lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is [...] Read more.
Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation. The acute phase (24–48 h) after TBI is often characterized by neural dysfunction in the vicinity of the lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is crucial for synaptic long-term plasticity including the protein degradation systems, proteasome and autophagy. Still, little is known about the acute effects of TBI on synaptic long-term plasticity and protein degradation. Thus, we investigated TBI in a controlled cortical impact (CCI) model in the motor and somatosensory cortex of mice ex vivo-in vitro. Late long-term potentiation (l-LTP) was induced by theta-burst stimulation in acute brain slices after survival times of 1–2 days. Protein levels for the plasticity related protein calcium/calmodulin-dependent protein kinase II (CaMKII) was quantified by Western blots, and the protein degradation activity by enzymatical assays. We observed missing maintenance of l-LTP in the ipsilateral hemisphere, however not in the contralateral hemisphere after TBI. Protein levels of CaMKII were not changed but, interestingly, the protein degradation revealed bidirectional changes with a reduced proteasome activity and an increased autophagic flux in the ipsilateral hemisphere. Finally, LTP recordings in the presence of pharmacologically modified protein degradation systems also led to an impaired synaptic plasticity: bath-applied MG132, a proteasome inhibitor, or rapamycin, an activator of autophagy, both administered during theta burst stimulation, blocked the induction of LTP. These data indicate that alterations in protein degradation pathways likely contribute to cognitive deficits in the acute phase after TBI, which could be interesting for future approaches towards neuroprotective treatments early after traumatic brain injury. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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Open AccessArticle
Assessing the Impact of Single-Cell Stimulation on Local Networks in Rat Barrel Cortex—A Feasibility Study
Int. J. Mol. Sci. 2019, 20(10), 2604; https://doi.org/10.3390/ijms20102604 - 27 May 2019
Abstract
In contrast to the long-standing notion that the role of individual neurons in population activity is vanishingly small, recent studies have shown that electrical activation of only a single cortical neuron can have measurable effects on global brain state, movement, and perception. Although [...] Read more.
In contrast to the long-standing notion that the role of individual neurons in population activity is vanishingly small, recent studies have shown that electrical activation of only a single cortical neuron can have measurable effects on global brain state, movement, and perception. Although highly important for understanding how neuronal activity in cortex is orchestrated, the cellular and network mechanisms underlying this phenomenon are unresolved. Here, we first briefly review the current state of knowledge regarding the phenomenon of single-cell induced network modulation and discuss possible underpinnings. Secondly, we show proof of principle for an experimental approach to elucidate the mechanisms of single-cell induced changes in cortical activity. The setup allows simultaneous recordings of the spiking activity of multiple neurons across all layers of the cortex using a multi-electrode array, while manipulating the activity of one individual neuron in close proximity to the array. We demonstrate that single cells can be recorded and stimulated reliably for hundreds of trials, conferring high statistical power even for expectedly small effects of single-neuron spiking on network activity. Preliminary results suggest that single-cell stimulation on average decreases the firing rate of local network units. We expect that characterization of the spatiotemporal spread of single-cell evoked activity across layers and columns will yield novel insights into intracortical processing. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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Open AccessArticle
Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl-Transport Shape Activity-Dependent Changes of Intracellular Cl Concentration
Int. J. Mol. Sci. 2019, 20(6), 1416; https://doi.org/10.3390/ijms20061416 - 20 Mar 2019
Cited by 2
Abstract
The effects of ionotropic γ-aminobutyric acid receptor (GABA-A, GABAA) activation depends critically on the Cl-gradient across neuronal membranes. Previous studies demonstrated that the intracellular Cl-concentration ([Cl]i) is not stable but shows a considerable [...] Read more.
The effects of ionotropic γ-aminobutyric acid receptor (GABA-A, GABAA) activation depends critically on the Cl-gradient across neuronal membranes. Previous studies demonstrated that the intracellular Cl-concentration ([Cl]i) is not stable but shows a considerable amount of activity-dependent plasticity. To characterize how membrane properties and different molecules that are directly or indirectly involved in GABAergic synaptic transmission affect GABA-induced [Cl]i changes, we performed compartmental modeling in the NEURON environment. These simulations demonstrate that GABA-induced [Cl]i changes decrease at higher membrane resistance, revealing a sigmoidal dependency between both parameters. Increase in GABAergic conductivity enhances [Cl]i with a logarithmic dependency, while increasing the decay time of GABAA receptors leads to a nearly linear enhancement of the [Cl]i changes. Implementing physiological levels of HCO3-conductivity to GABAA receptors enhances the [Cl]i changes over a wide range of [Cl]i, but this effect depends on the stability of the HCO3 gradient and the intracellular pH. Finally, these simulations show that pure diffusional Cl-elimination from dendrites is slow and that a high activity of Cl-transport is required to improve the spatiotemporal restriction of GABA-induced [Cl]i changes. In summary, these simulations revealed a complex interplay between several key factors that influence GABA-induced [Cl]i changes. The results suggest that some of these factors, including high resting [Cl]i, high input resistance, slow decay time of GABAA receptors and dynamic HCO3 gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl]i decreases. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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Review

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Open AccessReview
AMPA Receptor Auxiliary Proteins of the CKAMP Family
Int. J. Mol. Sci. 2019, 20(6), 1460; https://doi.org/10.3390/ijms20061460 - 22 Mar 2019
Cited by 1
Abstract
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are assembled of four core subunits and several additional interacting proteins. Cystine-knot AMPA receptor-modulating proteins (CKAMPs) constitute a family of four proteins that influence the trafficking, subcellular localization and function of AMPA receptors. The four CKAMP family members CKAMP39/shisa8, [...] Read more.
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are assembled of four core subunits and several additional interacting proteins. Cystine-knot AMPA receptor-modulating proteins (CKAMPs) constitute a family of four proteins that influence the trafficking, subcellular localization and function of AMPA receptors. The four CKAMP family members CKAMP39/shisa8, CKAMP44/shisa9, CKAMP52/shisa6 and CKAMP59/shisa7 differ in their expression profile and their modulatory influence on AMPA receptor function. In this review, I report about recent findings on the differential roles of CKAMP family members. Full article
(This article belongs to the Special Issue Rhine-Main Neuroscience Network: rmn^2-Oberwesel 2018)
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