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Hilscher, Markus M
Alternative names
Publications (7 of 7) Show all publications
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
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
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
Patra, K., Lyons, D. J., Bauer, P., Hilscher, M. M., Sharma, S., Leão, R. N. & Kullander, K. (2015). A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.. European Journal of Neuroscience, 41(3), 316-327
Open this publication in new window or tab >>A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.
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2015 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 41, no 3, p. 316-327Article in journal (Refereed) Published
Abstract [en]

The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-239636 (URN)10.1111/ejn.12790 (DOI)000349150000004 ()25410831 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2018-01-11Bibliographically approved
Perry, S., Gezelius, H., Larhammar, M., Hilscher, M. M., d'Incamps, B. L., Leao, K. E. & Kullander, K. (2015). Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents I-h and I-SK. European Journal of Neuroscience, 41(7), 887-898
Open this publication in new window or tab >>Firing properties of Renshaw cells defined by Chrna2 are modulated by hyperpolarizing and small conductance ion currents I-h and I-SK
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2015 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 41, no 7, p. 887-898Article in journal (Refereed) Published
Abstract [en]

Renshaw cells in the spinal cord ventral horn regulate motoneuron output through recurrent inhibition. Renshaw cells can be identified in vitro using anatomical and cellular criteria; however, their functional role in locomotion remains poorly defined because of the difficulty of functionally isolating Renshaw cells from surrounding motor circuits. Here we aimed to investigate whether the cholinergic nicotinic receptor alpha2 (Chrna2) can be used to identify Renshaw cells (RCs2) in the mouse spinal cord. Immunohistochemistry and electrophysiological characterization of passive and active RCs2 properties confirmed that neurons genetically marked by the Chrna2-Cre mouse line together with a fluorescent reporter mouse line are Renshaw cells. Whole-cell patch-clamp recordings revealed that RCs2 constitute an electrophysiologically stereotyped population with a resting membrane potential of -50.5 +/- 0.4mV and an input resistance of 233.1 +/- 11M. We identified a ZD7288-sensitive hyperpolarization-activated cation current (I-h) in all RCs2, contributing to membrane repolarization but not to the resting membrane potential in neonatal mice. Additionally, we found RCs2 to express small calcium-activated potassium currents (I-SK) that, when blocked by apamin, resulted in a complete attenuation of the afterhyperpolarisation potential, increasing cellular firing frequency. We conclude that RCs2 can be genetically targeted through their selective Chrna2 expression and that they display currents known to modulate rebound excitation and firing frequency. The genetic identification of Renshaw cells and their electrophysiological profile is required for genetic and pharmacological manipulation as well as computational simulations with the aim to understand their functional role.

Keywords
interneurons, mouse, nicotinic acetylcholine receptor alpha2, recurrent inhibition, spinal cord
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-252184 (URN)10.1111/ejn.12852 (DOI)000352540800003 ()
Available from: 2015-05-06 Created: 2015-05-04 Last updated: 2018-01-11Bibliographically approved
Mikulovic, S., Restrepo, E. C., Hilscher, M. M., Kullander, K. & Leao, R. N. (2015). Novel markers for OLM interneurons in the hippocampus. Frontiers in Cellular Neuroscience, 9, Article ID 201.
Open this publication in new window or tab >>Novel markers for OLM interneurons in the hippocampus
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2015 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 9, article id 201Article in journal, Editorial material (Other academic) Published
Keywords
interneuron, OLM, somatostatin, hippocampus, Chrna2
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-259200 (URN)10.3389/fncel.2015.00201 (DOI)000357611600001 ()26082683 (PubMedID)
Available from: 2015-07-30 Created: 2015-07-29 Last updated: 2018-01-11Bibliographically approved
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