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Perry, S., Larhammar, M., Vieillard, J., Nagaraja, C., Hilscher, M. M., Tafreshiha, A., . . . Kullander, K. (2019). Characterization of Dmrt3-Derived Neurons Suggest a Role within Locomotor Circuits. Journal of Neuroscience, 39(10), 1771-1782
Open this publication in new window or tab >>Characterization of Dmrt3-Derived Neurons Suggest a Role within Locomotor Circuits
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2019 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 10, p. 1771-1782Article in journal (Refereed) Published
Abstract [en]

Neuronal networks within the spinal cord, collectively known as the central pattern generator (CPG), coordinate rhythmic movements underlying locomotion. The transcription factor doublesex and mab-3-related transcription factor 3 (DMRT3) is involved in the differentiation of the dorsal interneuron 6 class of spinal cord interneurons. In horses, a non-sense mutation in the Dmrt3 gene has major effects on gaiting ability, whereas mice lacking the Dmrt3 gene display impaired locomotor activity. Although the Dmrt3 gene is necessary for normal spinal network formation and function in mice, a direct role for Dmrt3-derived neurons in locomotor-related activities has not been demonstrated. Here we present the characteristics of the Dmrt3-derived spinal cord interneurons. Using transgenic mice of both sexes, we characterized interneurons labeled by their expression of Cre driven by the endogenous Dmrt3 promoter. We used molecular, retrograde tracing and electrophysiological techniques to examine the anatomical, morphological, and electrical properties of the Dmrt3-Cre neurons. We demonstrate that inhibitory Dmrt3-Cre neurons receive extensive synaptic inputs, innervate surrounding CPG neurons, intrinsically regulate CPG neuron's electrical activity, and are rhythmically active during fictive locomotion, bursting at frequencies independent to the ventral root output. The present study provides novel insights on the character of spinal Dmrt3-derived neurons, data demonstrating that these neurons participate in locomotor coordination.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE, 2019
Keywords
central pattern generator, CPG, Dmrt3, interneuron, locomotion
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-379893 (URN)10.1523/JNEUROSCI.0326-18.2018 (DOI)000460403400002 ()30578339 (PubMedID)
Funder
The Swedish Brain FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-03-25Bibliographically approved
Defourny, J., Peuckert, C., Kullander, K. & Malgrange, B. (2019). EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through Local Disruption of Adherens Junctions. ISCIENCE, 11, 246-257
Open this publication in new window or tab >>EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through Local Disruption of Adherens Junctions
2019 (English)In: ISCIENCE, ISSN 2589-0042, Vol. 11, p. 246-257Article in journal (Refereed) Published
Abstract [en]

The cochlear sensory epithelium contains a functionally important triangular fluid-filled space between adjacent pillar cells referred to as the tunnel of Corti. However, the molecular mechanisms leading to local cell-cell separation during development remain elusive. Here we show that EphA4 associates with ADAM10 to promote the destruction of E-cadherin-based adhesions between adjacent pillar cells. These cells fail to separate from each other, and E-cadherin abnormally persists at the pillar cell junction in EphA4 forward-signaling-deficient mice, as well as in the presence of ADAM10 inhibitor. Using immunolabeling and an in situ proximity ligation assay, we found that EphA4 forms a complex with E-cadherin and its sheddase ADAM10, which could be activated by ephrin-B2 across the pillar cell junction to trigger the cleavage of E-cadherin. Altogether, our findings provide a new molecular insight into the regulation of adherens junctions, which might be extended to a variety of physiological or pathological processes.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-377351 (URN)10.1016/j.isci.2018.12.017 (DOI)000456942200018 ()30639848 (PubMedID)
Available from: 2019-02-22 Created: 2019-02-22 Last updated: 2019-02-22Bibliographically approved
Schnerwitzki, D., Perry, S., Ivanova, A., Caixeta, F. V., Cramer, P., Guenther, S., . . . Englert, C. (2018). Neuron-specific inactivation of Wt1 alters locomotion in mice and changes interneuron composition in the spinal cord. LIFE SCIENCE ALLIANCE, 1(4), Article ID e201800106.
Open this publication in new window or tab >>Neuron-specific inactivation of Wt1 alters locomotion in mice and changes interneuron composition in the spinal cord
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2018 (English)In: LIFE SCIENCE ALLIANCE, ISSN 2575-1077, Vol. 1, no 4, article id e201800106Article in journal (Refereed) Published
Abstract [en]

Locomotion is coordinated by neuronal circuits of the spinal cord. Recently, dI6 neurons were shown to participate in the control of locomotion. A subpopulation of dI6 neurons expresses the Wilms tumor suppressor gene Wt1. However, the function of Wt1 in these cells is not understood. Here, we aimed to identify behavioral changes and cellular alterations in the spinal cord associated with Wt1 deletion. Locomotion analyses of mice with neuron-specific Wt1 deletion revealed a slower walk with a decreased stride frequency and an increased stride length. These mice showed changes in their fore-/hindlimb coordination, which were accompanied by a loss of contralateral projections in the spinal cord. Neonates with Wt1 deletion displayed an increase in uncoordinated hindlimb movements and their motor neuron output was arrhythmic with a decreased frequency. The population size of dI6, V0, and V2a neurons in the developing spinal cord of conditional Wt1 mutants was significantly altered. These results show that the development of particular dI6 neurons depends on Wt1 expression and that loss of Wt1 is associated with alterations in locomotion.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-377292 (URN)10.26508/lsa.201800106 (DOI)000457327700010 ()30456369 (PubMedID)
Funder
The Swedish Brain Foundation
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-18Bibliographically approved
Siwani, S., Franca, A. S. C., Mikulovic, S., Reis, A., Hilscher, M. M., Edwards, S. J., . . . Kullander, K. (2018). OLM alpha 2 Cells Bidirectionally Modulate Learning. Neuron, 99(2), 404-412
Open this publication in new window or tab >>OLM alpha 2 Cells Bidirectionally Modulate Learning
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2018 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 99, no 2, p. 404-412Article in journal (Refereed) Published
Abstract [en]

Inhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor alpha 2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLM alpha 2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLM alpha 2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLM alpha 2 cell activation inhibits fear-related memories and that OLM alpha 2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLM alpha 2 cells are an important component in the CA1 microcircuit regulating learning and memory processes.

Place, publisher, year, edition, pages
CELL PRESS, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-387269 (URN)10.1016/j.neuron.2018.06.022 (DOI)000439709900017 ()29983324 (PubMedID)
Funder
Swedish Research Council, 2015-02395
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Boije, H. & Kullander, K. (2018). Origin and circuitry of spinal locomotor interneurons generating different speeds.. Current Opinion in Neurobiology, 53, 16-21
Open this publication in new window or tab >>Origin and circuitry of spinal locomotor interneurons generating different speeds.
2018 (English)In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 53, p. 16-21Article in journal (Refereed) Published
Abstract [en]

The spinal circuitry governing the undulatory movements of swimming vertebrates consist of excitatory and commissural inhibitory interneurons and motor neurons. This locomotor network generates the rhythmic output, coordinate left/right alternation, and permit communication across segments. Through evolution, more complex movement patterns have emerged, made possible by sub-specialization of neural populations within the spinal cord. Walking tetrapods use a similar basic circuitry, but have added layers of complexity for the coordination of intralimbic flexor and extensor muscles as well as interlimbic coordination between the body halves and fore/hindlimbs. Although the basics of these circuits are known there is a gap in our knowledge regarding how different speeds and gaits are coordinated. Analysing subpopulations among described neuronal populations may bring insight into how changes in locomotor output are orchestrated by a hard-wired network.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-367220 (URN)10.1016/j.conb.2018.04.024 (DOI)000451938500004 ()29733915 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2018-11-29 Created: 2018-11-29 Last updated: 2019-01-28Bibliographically approved
Benlloch, J. M., Gonzalez, A. J., Pani, R., Preziosi, E., Jackson, C., Murphy, J., . . . Schwaiger, M. (2018). The MINDVIEW project: First results. European psychiatry, 50, 21-27
Open this publication in new window or tab >>The MINDVIEW project: First results
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2018 (English)In: European psychiatry, ISSN 0924-9338, E-ISSN 1778-3585, Vol. 50, p. 21-27Article in journal (Refereed) Published
Abstract [en]

We present the first results of the MINDVIEW project. An innovative imaging system for the human brain examination, allowing simultaneous acquisition of PET/MRI images, has been designed and constructed. It consists of a high sensitivity and high resolution PET scanner integrated in a novel, head-dedicated, radio frequency coil for a 3T MRI scanner. Preliminary measurements from the PET scanner show sensitivity 3 times higher than state-of-the-art PET systems that will allow safe repeated studies on the same patient. The achieved spatial resolution, close to 1 mm, will enable differentiation of relevant brain structures for schizophrenia. A cost-effective and simple method of radiopharmaceutical production from 11C-carbon monoxide and a mini-clean room has been demonstrated. It has been shown that 11C-raclopride has higher binding potential in a new VAAT null mutant mouse model of schizophrenia compared to wild type control animals. A significant reduction in TSPO binding has been found in gray matter in a small sample of drug-naïve, first episode psychosis patients, suggesting a reduced number or an altered function of immune cells in brain at early stage schizophrenia.

Keywords
Schizophrenia, Positron Emission Tomography, Silicon photomultipliers and magnetic resonance
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-353215 (URN)10.1016/j.eurpsy.2018.01.002 (DOI)000430263900004 ()29398564 (PubMedID)
Available from: 2018-06-13 Created: 2018-06-13 Last updated: 2018-06-13Bibliographically approved
Mikulovic, S., Restrepo, C. E., Siwani, S., Bauer, P., Johann, S. P., Tort, A. B. L., . . . Leão, R. N. (2018). Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor. Nature Communications, 9, 3638:1-15, Article ID 3638.
Open this publication in new window or tab >>Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, p. 3638:1-15, article id 3638Article in journal (Refereed) Published
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:uu:diva-364241 (URN)10.1038/s41467-018-05907-w (DOI)000444014100013 ()30194386 (PubMedID)
Projects
eSSENCE
Available from: 2018-09-07 Created: 2018-10-29 Last updated: 2018-10-30Bibliographically approved
Hilscher, M. M., Leão, R. N., Edwards, S. J., Leão, K. E. & Kullander, K. (2017). Chrna2-Martinotti Cells Synchronize Layer 5 Type A Pyramidal Cells via Rebound Excitation. PLoS biology, 15(2), Article ID e2001392.
Open this publication in new window or tab >>Chrna2-Martinotti Cells Synchronize Layer 5 Type A Pyramidal Cells via Rebound Excitation
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2017 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 2, article id e2001392Article in journal (Refereed) Published
Abstract [en]

Martinotti cells are the most prominent distal dendrite-targeting interneurons in the cortex, but their role in controlling pyramidal cell ( PC) activity is largely unknown. Here, we show that the nicotinic acetylcholine receptor alpha 2 subunit (Chrna2) specifically marks layer 5 (L5) Martinotti cells projecting to layer 1. Furthermore, we confirm that Chrna2-expressing Martinotti cells selectively target L5 thick-tufted type A PCs but not thin-tufted type B PCs. Using optogenetic activation and inhibition, we demonstrate how Chrna2-Martinotti cells robustly reset and synchronize type A PCs via slow rhythmic burst activity and rebound excitation. Moreover, using optical feedback inhibition, in which PC spikes controlled the firing of surrounding Chrna2-Martinotti cells, we found that neighboring PC spike trains became synchronized by Martinotti cell inhibition. Together, our results show that L5 Martinotti cells participate in defined cortical circuits and can synchronize PCs in a frequency-dependent manner. These findings suggest that Martinotti cells are pivotal for coordinated PC activity, which is involved in cortical information processing and cognitive control.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-319126 (URN)10.1371/journal.pbio.2001392 (DOI)000395719500005 ()28182735 (PubMedID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-04-03 Created: 2017-04-03 Last updated: 2017-11-29Bibliographically approved
Enjin, A., Perry, S., Hilscher, M. M., Nagaraja, C., Larhammar, M., Gezelius, H., . . . Kullander, K. (2017). Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit. Journal of Neuroscience, 37(23), 5634-5647
Open this publication in new window or tab >>Developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw cell-motor neuron circuit
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2017 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 23, p. 5634-5647Article in journal (Refereed) Published
Abstract [en]

When activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor α2 (Chrna2) in mice to genetically target the vesicular inhibitory amino acid transporter (VIAAT) in Renshaw cells. Loss of VIAAT from Chrna2Cre-expressing Renshaw cells did not impact any aspect of drug-induced fictive locomotion in the neonatal mouse or change gait, motor coordination, or grip strength in adult mice of both sexes. However, motor neurons from neonatal mice lacking VIAAT in Renshaw cells received spontaneous inhibitory synaptic input with a reduced frequency, showed lower input resistance, and had an increased number of proprioceptive glutamatergic and calbindin-labeled putative Renshaw cell synapses on their soma and proximal dendrites. Concomitantly, Renshaw cells developed with increased excitability and a normal number of cholinergic motor neuron synapses, indicating a compensatory mechanism within the recurrent inhibitory feedback circuit. Our data suggest an integral role for Renshaw cell signaling in shaping the excitability and synaptic input to motor neurons.

Keywords
ChAT, Chrna2, mouse, spinal cord, VIAAT
National Category
Developmental Biology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-305237 (URN)10.1523/JNEUROSCI.0949-16.2017 (DOI)000402907200007 ()28483975 (PubMedID)
Funder
The Swedish Brain FoundationThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2016-10-19 Created: 2016-10-13 Last updated: 2017-08-14Bibliographically approved
Schizas, N., Perry, S., Andersson, B., Wählby, C., Kullander, K. & Hailer, N. (2017). Differential neuroprotective effects of interleukin-1 receptor antagonist on spinal cord neurons after excitotoxic injury. Neuroimmunomodulation, 24, 220-230
Open this publication in new window or tab >>Differential neuroprotective effects of interleukin-1 receptor antagonist on spinal cord neurons after excitotoxic injury
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2017 (English)In: Neuroimmunomodulation, ISSN 1021-7401, E-ISSN 1423-0216, Vol. 24, p. 220-230Article in journal (Refereed) Published
National Category
Neurosciences Medical Image Processing
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-251475 (URN)10.1159/000484607 (DOI)000428694500004 ()29393213 (PubMedID)
Available from: 2018-01-26 Created: 2015-04-19 Last updated: 2018-06-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6418-5460

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