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Philippe Ascher - One of the best experts on this subject based on the ideXlab platform.
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segregation of glutamatergic and cholinergic transmission at the mixed motoneuron Renshaw Cell synapse
Scientific Reports, 2017Co-Authors: Boris Lamotte Dincamps, Gardave S Bhumbra, Joshua D Foster, Marco Beato, Philippe AscherAbstract:In neonatal mice motoneurons excite Renshaw Cells by releasing both acetylcholine (ACh) and glutamate. These two neurotransmitters activate two types of nicotinic receptors (nAChRs) (the homomeric α7 receptors and the heteromeric α*s* receptors) as well as the two types of glutamate receptors (GluRs) (AMPARs and NMDARs). Using paired recordings, we confirm that a single motoneuron can release both transmitters on a single post-synaptic Renshaw Cell. We then show that co-transmission is preserved in adult animals. Kinetic analysis of miniature EPSCs revealed quantal release of mixed events associating AMPARs and NMDARs, as well as α7 and α*s* nAChRs, but no evidence was found for mEPSCs associating nAChRs with GluRs. Bayesian Quantal Analysis (BQA) of evoked EPSCs showed that the number of functional contacts on a single Renshaw Cell is more than halved when the nicotinic receptors are blocked, confirming that the two neurotransmitters systems are segregated. Our observations can be explained if ACh and glutamate are released from common vesicles onto spatially segregated post-synaptic receptors clusters, but a pre-synaptic segregation of cholinergic and glutamatergic release sites is also possible.
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subunit composition and kinetics of the Renshaw Cell heteromeric nicotinic receptors
Biochemical Pharmacology, 2013Co-Authors: Boris Lamotte Dincamps, Philippe AscherAbstract:Abstract In Renshaw Cells (RCs) of newborn mice, activation of motoneurons elicits a four-component synaptic current (EPSC) mediated by two glutamate receptors and two nicotinic receptors (nAChRs). We have analyzed the nicotinic component of the EPSC which is blocked by dihydro-beta-erythroidine (DHβE) with the dual objective of identifying the nAChR subunits involved and of understanding the kinetics of the response. The sensitivity to DHβE of the peak of the EPSC was differentially affected by genetic deletion of three specific nAChR subunits: α2, β2 and β4. The comparison of these effects with published findings on recombinant receptors suggests that, in WT mice, two heteromeric assemblies, α4β2 and α2β4, coexist in variable proportions in a given RC. Some results seem to require, however, the involvement of an additional subunit. The effects of DHβE on the decay of the EPSCs were compared in WT mice and in PRiMA−/− mice, in which the decay is prolonged by the absence of central acetylcholinesterase. In PRiMA−/− mice DHβE shortened the decay of the EPSC. In WT mice it did not alter the decay but reduced the amplitude of both components of the EPSC. The results can be interpreted by assuming that the nAChRs exist in two stoichiometries, subsynaptic “low sensitivity” nAChRs and extrasynaptic “high sensitivity” nAChRs activated by spillover.
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mechanisms shaping the slow nicotinic synaptic current at the motoneuron Renshaw Cell synapse
The Journal of Neuroscience, 2012Co-Authors: Boris Lamotte Dincamps, Eric Krejci, Philippe AscherAbstract:In spinal cord slices from newborn mice we have analyzed the kinetics of the EPSCs mediated by heteromeric nicotinic receptors at the motoneuron–Renshaw Cell (MN-RC) synapse. The miniature EPSCs decay with a time constant of 13.0 ± 1.1 ms whereas the decay of the evoked EPSCs (eEPSCs) is biphasic, with time constants of 15.6 ± 0.8 and 124.8 ± 9.0 ms. The slow component becomes prominent during a repetitive stimulation, but its time constant is unchanged. It is selectively reduced by the addition of acetylcholinesterase (AChE), and thus appears to involve ACh spillover. The constancy of the slow time constant during a train is best explained by a local spillover activating high-affinity receptors. In many Cells a fraction of the eEPSC originates in neighboring RCs and is transmitted by the low-pass filter of the gap junctions. The component transmitted electrically can be eliminated by meclofenamic acid, a blocker of gap junctions. The local spillover produced by a repetitive stimulation was compared with the long-range spillover produced by inactivation of AChE. The pharmacological inactivation of AChE by neostigmine caused the appearance of an ultra-slow (second range) decay component in eEPSCs and also a continuous inward current interpreted as resulting from a continuous ACh presence. In animals lacking functional AChE in the CNS (PRiMA−/− mice) the EPSCs resembled those observed in neostigmine but the steady inward current was much smaller, suggesting an adaptation to the absence of AChE.
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four excitatory postsynaptic ionotropic receptors coactivated at the motoneuron Renshaw Cell synapse
The Journal of Neuroscience, 2008Co-Authors: Boris Lamotte Dincamps, Philippe AscherAbstract:Renshaw Cells (RCs) are spinal interneurons excited by collaterals of the axons of motoneurons (MNs). They respond to a single motoneuronal volley by a surprisingly long (tens of milliseconds) train of action potentials. We have analyzed this synaptic response in spinal cord slices of neonatal mice in light of recent observations suggesting that the MN axons release both acetylcholine and glutamate. We found that the RC synaptic current involves four components of similar amplitudes mediated by two nicotinic receptors (nAChRs, tentatively identified as α 7 homomers and α 4 β 2 heteromers) and two glutamate receptors (AMPARs and NMDARs). The decay time constants of the four components cover a wide range: from 3.6 ± 2.2 ms (α 7 nAChRs) to 54.6 ± 19.5 ms (NMDARs, at −45 mV). The RC discharge can be separated into an initial doublet of high-frequency action potentials followed by later spikes with a variable latency and longer interspike intervals. The initial doublet involves the four ionotropic receptors as well as endogenous voltage-dependent conductances. The late discharge depends on NMDARs, but these receptors must be primed by the initial depolarization. The activation of the NMDARs is prolonged by the fact that their slow deactivation is further slowed by depolarization. The formation of the initial doublet is favored by hyperpolarization, whereas the late discharge is favored by depolarization. This suggests that in physiological conditions the pattern of discharge of the RC in response to a MN input may alternate between a phasic and a tonic response.
Boris Lamotte Dincamps - One of the best experts on this subject based on the ideXlab platform.
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stoichiometry of the heteromeric nicotinic receptors of the Renshaw Cell
The Journal of Neuroscience, 2018Co-Authors: Boris Lamotte Dincamps, Eric Krejci, Tamara Zorbaz, Dominika Dingova, P AscherAbstract:Neuronal nicotinic acetylcholine receptors (nAChRs) are pentamers built from a variety of subunits. Some are homomeric assemblies of α subunits, others heteromeric assemblies of α and β subunits which can adopt two stoichiometries (2α:3β or 3α:2β). There is evidence for the presence of heteromeric nAChRs with the two stoichiometries in the CNS, but it has not yet been possible to identify them at a given synapse. The 2α:3β receptors are highly sensitive to agonists, whereas the 3α:2β stoichiometric variants, initially described as low sensitivity receptors, are in fact activated by low and high concentrations of ACh. We have taken advantage of the discovery that two compounds — NS9283 and Zn — potentiate selectively the 3α:2β nAChRs to establish (in mice of either sex) the presence of these variants at the motoneuron-Renshaw Cell (MN-RC) synapse. NS9283 prolonged the decay of the two-component EPSC mediated by heteromeric nAChRs. NS9283 and Zn also prolonged spontaneous EPSCS involving heteromeric nAChRs, and one could rule out prolongations resulting from AChE inhibition by NS9283. These results establish the presence of 3α:2β nAChRs at the MN-RC synapse. At the functional level we had previously explained the duality of the EPSC by assuming that high ACh concentrations in the synaptic cleft account for the fast component and that spillover of ACh accounts for the slow component. The dual ACh sensitivity of 3α:2β nAChRs now allows to attribute to these receptors both components of the EPSC. SIGNIFICANCE STATEMENT Heteromeric nicotinic receptors assemble α and β subunits in pentameric structures which can adopt two stoichiometries: 3α:2β or 2α:3β. Both stoichiometric variants are present in the central nervous system but they have never been located and characterized functionally at the level of an identified synapse. Our data indicate that 3α:2β receptors are present at the spinal cord synapses between motoneurons and Renshaw Cells, where their dual mode of activation (by high concentrations of ACh for synaptic receptors, by low concentrations of ACh for extrasynaptic receptors) likely accounts for the biphasic character of the synaptic current. More generally, 3α:2β nicotinic receptors appear unique by their capacity to operate both in the cleft of classical synapses and at extra-synaptic locations.
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segregation of glutamatergic and cholinergic transmission at the mixed motoneuron Renshaw Cell synapse
Scientific Reports, 2017Co-Authors: Boris Lamotte Dincamps, Gardave S Bhumbra, Joshua D Foster, Marco Beato, Philippe AscherAbstract:In neonatal mice motoneurons excite Renshaw Cells by releasing both acetylcholine (ACh) and glutamate. These two neurotransmitters activate two types of nicotinic receptors (nAChRs) (the homomeric α7 receptors and the heteromeric α*s* receptors) as well as the two types of glutamate receptors (GluRs) (AMPARs and NMDARs). Using paired recordings, we confirm that a single motoneuron can release both transmitters on a single post-synaptic Renshaw Cell. We then show that co-transmission is preserved in adult animals. Kinetic analysis of miniature EPSCs revealed quantal release of mixed events associating AMPARs and NMDARs, as well as α7 and α*s* nAChRs, but no evidence was found for mEPSCs associating nAChRs with GluRs. Bayesian Quantal Analysis (BQA) of evoked EPSCs showed that the number of functional contacts on a single Renshaw Cell is more than halved when the nicotinic receptors are blocked, confirming that the two neurotransmitters systems are segregated. Our observations can be explained if ACh and glutamate are released from common vesicles onto spatially segregated post-synaptic receptors clusters, but a pre-synaptic segregation of cholinergic and glutamatergic release sites is also possible.
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subunit composition and kinetics of the Renshaw Cell heteromeric nicotinic receptors
Biochemical Pharmacology, 2013Co-Authors: Boris Lamotte Dincamps, Philippe AscherAbstract:Abstract In Renshaw Cells (RCs) of newborn mice, activation of motoneurons elicits a four-component synaptic current (EPSC) mediated by two glutamate receptors and two nicotinic receptors (nAChRs). We have analyzed the nicotinic component of the EPSC which is blocked by dihydro-beta-erythroidine (DHβE) with the dual objective of identifying the nAChR subunits involved and of understanding the kinetics of the response. The sensitivity to DHβE of the peak of the EPSC was differentially affected by genetic deletion of three specific nAChR subunits: α2, β2 and β4. The comparison of these effects with published findings on recombinant receptors suggests that, in WT mice, two heteromeric assemblies, α4β2 and α2β4, coexist in variable proportions in a given RC. Some results seem to require, however, the involvement of an additional subunit. The effects of DHβE on the decay of the EPSCs were compared in WT mice and in PRiMA−/− mice, in which the decay is prolonged by the absence of central acetylcholinesterase. In PRiMA−/− mice DHβE shortened the decay of the EPSC. In WT mice it did not alter the decay but reduced the amplitude of both components of the EPSC. The results can be interpreted by assuming that the nAChRs exist in two stoichiometries, subsynaptic “low sensitivity” nAChRs and extrasynaptic “high sensitivity” nAChRs activated by spillover.
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mechanisms shaping the slow nicotinic synaptic current at the motoneuron Renshaw Cell synapse
The Journal of Neuroscience, 2012Co-Authors: Boris Lamotte Dincamps, Eric Krejci, Philippe AscherAbstract:In spinal cord slices from newborn mice we have analyzed the kinetics of the EPSCs mediated by heteromeric nicotinic receptors at the motoneuron–Renshaw Cell (MN-RC) synapse. The miniature EPSCs decay with a time constant of 13.0 ± 1.1 ms whereas the decay of the evoked EPSCs (eEPSCs) is biphasic, with time constants of 15.6 ± 0.8 and 124.8 ± 9.0 ms. The slow component becomes prominent during a repetitive stimulation, but its time constant is unchanged. It is selectively reduced by the addition of acetylcholinesterase (AChE), and thus appears to involve ACh spillover. The constancy of the slow time constant during a train is best explained by a local spillover activating high-affinity receptors. In many Cells a fraction of the eEPSC originates in neighboring RCs and is transmitted by the low-pass filter of the gap junctions. The component transmitted electrically can be eliminated by meclofenamic acid, a blocker of gap junctions. The local spillover produced by a repetitive stimulation was compared with the long-range spillover produced by inactivation of AChE. The pharmacological inactivation of AChE by neostigmine caused the appearance of an ultra-slow (second range) decay component in eEPSCs and also a continuous inward current interpreted as resulting from a continuous ACh presence. In animals lacking functional AChE in the CNS (PRiMA−/− mice) the EPSCs resembled those observed in neostigmine but the steady inward current was much smaller, suggesting an adaptation to the absence of AChE.
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development of spinal motor circuits in the absence of viaat mediated Renshaw Cell signaling
2011Co-Authors: Anders Enjin, Chetan Nagaraja, Martin Larhammar, Henrik Gezelius, Anders Eriksson, Katarina E Leao, Boris Lamotte Dincamps, Klas KullanderAbstract:Movement is central for life, and all animals depend on accurate regulation of movement for purposeful behavior. There is great diversity of movements, ranging between simple and vital breathing movements to minute and subtle movements of the face used to communicate emotions. Consequently, motor neurons, which are the only route of central nervous system output, are essential for all motor behaviors. To control the many motor behaviors expressed by an animal, motor neurons are exposed to a large number and variety of modulating synaptic inputs and have evolved into subtypes with specific functions. In this thesis, motor neuron subtypes and the synaptic input to motor neurons from Renshaw Cells and Ia afferents have been studied. Novel molecular markers that identify subtypes of motor neurons are described. Three markers, Chodl, Calca and ERRβ, have been used to study the degeneration of subtypes of motor neurons in a mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Another marker, 5-ht1d, has been used to record the electrophysiological character of gamma motor neurons. In mice that lack 5-ht1d, motor neurons develop with reduced proprioceptive input. Remarkably, these mice had fewer foot faults than control animals when challenged to cross a narrow beam suggesting that the amplitude of monosynaptic proprioceptive input to motor neurons is not essential for motor coordination. In a final set of experiments, genetic removal of vesicular transport of neurotransmitter from Renshaw Cells suggest that Renshaw Cells are not integral for motor circuit function or motor behaviors. However, they are involved in the development of motor circuits in the spinal cord. Together, this thesis provides novel molecular tools for studies of motor neuron subtypes and novel data regarding the development and function of spinal motor circuits.
Uwe Windhorst - One of the best experts on this subject based on the ideXlab platform.
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Effects of spinal recurrent inhibition on motoneuron short-term synchronization
Biological Cybernetics, 2007Co-Authors: Takanori Uchiyama, Uwe WindhorstAbstract:Spinal recurrent inhibition linking skeleto- motoneurons ( α -MNs) via Renshaw Cells (RCs) has been variously proposed to increase or decrease tendencies toward synchronous discharges between α -MNs. This controversy is not easy to settle experimentally in animal or human paradigms because RCs receive, in addition to excitatory input from α -MNs, many other modulating influences which may change their mode of operation. Computer simulations help to artificially isolate the recurrent inhibitory circuit and thus to study its effects on α -MN synchronization under conditions not achievable in natural experiments. We present here such a study which was designed to specifically test the following hypothesis. Since many α -MNs excite any particular Renshaw Cell, which in turn inhibits many α -MNs, this convergence–divergence pattern establishes a random network whose random discharge patterns inject uncorrelated noise into α -MNs, and this noise counteracts any synchronization potentially arising from other sources, e.g., common inputs (Adam et al. in Biol Cybern 29:229–235, 1978). We investigated the short-term synchronization of α -MNs with two types of excitatory input signals to α -MNs (random and sinusoidally modulated random patterns). The main results showed that, while recurrent inhibitory inputs to different α -MNs were indeed different, recurrent inhibition (1) exerted rather small effects on the modulation of α -MN discharge, (2) tended to increase the short-term synchronization of α -MN discharge, and (3) did not generate secondary peaks in α -MN- α -MN cross-correlograms associated with α -MN rhythmicity.
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static and dynamic input output relations of the feline medial gastrocnemius motoneuron muscle system subjected to recurrent inhibition a model study
Biological Cybernetics, 2003Co-Authors: Takanori Uchiyama, Håkan Johansson, Uwe WindhorstAbstract:The physiological function of spinal recurrent inhibition is still a matter of debate because of the experimental difficulty or impossibility of observing recurrent inhibition at work in normally behaving animals. The purpose of this study was to investigate, by computer simulation, the role of recurrent inhibition in shaping the input-output (I/O) relationships between descending command signals (DCS) as inputs and motoneuron (MN) and Renshaw Cell (RC) firing rates and muscle force as outputs. Changing the spatial (topographical) distribution of recurrent inhibition from nonhomogeneous (as in the standard model) to homogeneous did not alter the I/O relationships significantly, while changing the functional distribution related to MN types did. Altering the global gain of recurrent inhibition, as happens naturally in various motor acts, changes the slopes and positions (at high inputs) of the I/O relationships, making recurrent inhibition a suitable means of gain control. Coupling a decrease in recurrent inhibitory gain with an increase in DCS input, as could occur during slow dynamic contractions, would increase the MN and force gains during the act. Short dynamic ramp-and-hold DCS inputs generate MN firing patterns, to which recurrent inhibition contributes interspike-interval variability and damped oscillations, which are related to issues of tremor and its control.
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Renshaw Cell responses to intra arterial injection of muscle metabolites into cat calf muscles
Neuroscience Research, 1997Co-Authors: Uwe Windhorst, J Meyerlohmann, Dov Kirmayer, Douglas W ZochodneAbstract:Abstract Metabolites released during fatiguing muscle contractions excite group III–IV muscle afferents which might inhibit skeleto-motoneuron firing, hypothetically via Renshaw Cells. This was tested, in decerebrated, spinalized cats, by recording changes in Renshaw Cell spontaneous discharges and responses to antidromic electrical stimulation of motor axons when small-diameter calf muscle afferents were excited by intra-arterially injected bradykinin, serotonin, lactic acid and KCl. Whenever such injections had an effect, it transiently raised or lowered the spontaneous firing rate and almost always decreased the antidromic response to motor axon stimulation. Injection of bradykinin and serotonin commonly decreased the blood pressure and concomitantly the spinal blood flow (as measured using laser Doppler flowmetry), which could have indirectly influenced Renshaw Cell firing. But in general, blood pressure and flow changed after the Renshaw Cell discharge did, which thus, appears to be modulated independently by group III–IV afferents. These results suggest that the Renshaw Cell-mediated effects of neurochemically excited afferents would predominantly disinhibit rather than inhibit motoneurons.
Francisco J Alvarez - One of the best experts on this subject based on the ideXlab platform.
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Role of primary afferents in the developmental regulation of motor axon synapse numbers on Renshaw Cells
The Journal of Comparative Neurology, 2016Co-Authors: Valerie C. Siembab, Travis M Rotterman, Laura Gomez-perez, Neil A. Shneider, Francisco J AlvarezAbstract:: Motor function in mammalian species depends on the maturation of spinal circuits formed by a large variety of interneurons that regulate motoneuron firing and motor output. Interneuron activity is in turn modulated by the organization of their synaptic inputs, but the principles governing the development of specific synaptic architectures unique to each premotor interneuron are unknown. For example, Renshaw Cells receive, at least in the neonate, convergent inputs from sensory afferents (likely Ia) and motor axons, raising the question of whether they interact during Renshaw Cell development. In other well-studied neurons, such as Purkinje Cells, heterosynaptic competition between inputs from different sources shapes synaptic organization. To examine the possibility that sensory afferents modulate synaptic maturation on developing Renshaw Cells, we used three animal models in which afferent inputs in the ventral horn are dramatically reduced (ER81(-/-) knockout), weakened (Egr3(-/-) knockout), or strengthened (mlcNT3(+/-) transgenic). We demonstrate that increasing the strength of sensory inputs on Renshaw Cells prevents their deselection and reduces motor axon synaptic density, and, in contrast, absent or diminished sensory afferent inputs correlate with increased densities of motor axons synapses. No effects were observed on other glutamatergic inputs. We conclude that the early strength of Ia synapses influences their maintenance or weakening during later development and that heterosynaptic influences from sensory synapses during early development regulates the density and organization of motor inputs on mature Renshaw Cells.
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Motor Axon Synapses on Renshaw Cells Contain Higher Levels of Aspartate than Glutamate
PLOS ONE, 2014Co-Authors: Dannette Shanon Richards, Ronald W. Griffith, Shannon H. Romer, Francisco J AlvarezAbstract:Motoneuron synapses on spinal cord interneurons known as Renshaw Cells activate nicotinic, AMPA and NMDA receptors consistent with co-release of acetylcholine and excitatory amino acids (EAA). However, whether these synapses express vesicular glutamate transporters (VGLUTs) capable of accumulating glutamate into synaptic vesicles is controversial. An alternative possibility is that these synapses release other EAAs, like aspartate, not dependent on VGLUTs. To clarify the exact EAA concentrated at motor axon synapses we performed a quantitative postembedding colloidal gold immunoelectron analysis for aspartate and glutamate on motor axon synapses (identified by immunoreactivity to the vesicular acetylcholine transporter; VAChT) contacting calbindin-immunoreactive (-IR) Renshaw Cell dendrites. The results show that 71% to 80% of motor axon synaptic boutons on Renshaw Cells contained aspartate immunolabeling two standard deviations above average neuropil labeling. Moreover, VAChT-IR synapses on Renshaw Cells contained, on average, aspartate immunolabeling at 2.5 to 2.8 times above the average neuropil level. In contrast, glutamate enrichment was lower; 21% to 44% of VAChT-IR synapses showed glutamate-IR two standard deviations above average neuropil labeling and average glutamate immunogold density was 1.7 to 2.0 times the neuropil level. The results were not influenced by antibody affinities because glutamate antibodies detected glutamate-enriched brain homogenates more efficiently than aspartate antibodies detecting aspartate-enriched brain homogenates. Furthermore, synaptic boutons with ultrastructural features of Type I excitatory synapses were always labeled by glutamate antibodies at higher density than motor axon synapses. We conclude that motor axon synapses co-express aspartate and glutamate, but aspartate is concentrated at higher levels than glutamate.
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alterations in the motor neuron Renshaw Cell circuit in the sod1g93a mouse model
The Journal of Comparative Neurology, 2013Co-Authors: Hanna Wootz, Anders Enjin, Martin Larhammar, Klas Kullander, Eileen Fitzsimonskantamneni, Travis M Rotterman, Kalicharan Patra, Elodie Andre, Brigitte Van Zundert, Francisco J AlvarezAbstract:: Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw Cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw Cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these Cells during disease progression in the Sod1(G93A) mouse model. Most calbindin-immunoreactive (IR) Renshaw Cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw Cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw Cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw Cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing. J. Comp. Neurol. 521:1449-1469, 2013. © 2012 Wiley Periodicals, Inc.
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Principles of interneuron development learned from Renshaw Cells and the motoneuron recurrent inhibitory circuit
Annals of the New York Academy of Sciences, 2013Co-Authors: Francisco J Alvarez, Ana Benito-gonzalez, Valerie C. SiembabAbstract:Renshaw Cells provide a convenient model to study spinal circuit development during the emergence of motor behaviors with the goal of capturing principles of interneuron specification and circuit construction. This work is facilitated by a long history of research that generated essential knowledge about the characteristics that define Renshaw Cells and the recurrent inhibitory circuit they form with motoneurons. In this review, we summarize recent data on the specification of Renshaw Cells and their connections. A major insight from these studies is that the basic Renshaw Cell phenotype is specified before circuit assembly, a result of their early neurogenesis and migration. Connectivity is later added, constrained by their placement in the spinal cord. Finally, different rates of synapse proliferation alter the relative weights of different inputs on postnatal Renshaw Cells. Based on this work some general principles on the integration of spinal interneurons in developing motor circuits are derived.
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the continuing case for the Renshaw Cell
The Journal of Physiology, 2007Co-Authors: Francisco J Alvarez, Robert E W FyffeAbstract:Renshaw Cell properties have been studied extensively for over 50 years, making them a uniquely well-defined class of spinal interneuron. Recent work has revealed novel ways to identify Renshaw Cells in situ and this in turn has promoted a range of studies that have determined their ontogeny and organization of synaptic inputs in unprecedented detail. In this review we illustrate how mature Renshaw Cell properties and connectivity arise through a combination of activity-dependent and genetically specified mechanisms. These new insights should aid the development of experimental strategies to manipulate Renshaw Cells in spinal circuits and clarify their role in modulating motor output.
Klas Kullander - One of the best experts on this subject based on the ideXlab platform.
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developmental disruption of recurrent inhibitory feedback results in compensatory adaptation in the Renshaw Cell motor neuron circuit
The Journal of Neuroscience, 2017Co-Authors: Anders Enjin, Sharn Perry, Markus M Hilscher, Chetan Nagaraja, Martin Larhammar, Henrik Gezelius, Anders Eriksson, Katarina E Leao, Klas KullanderAbstract: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. SIGNIFICANCE STATEMENT We here provide a deeper understanding of spinal cord circuit formation and the repercussions for the possible role for Renshaw Cells in speed and force control. Our results suggest that while Renshaw Cells are not directly required as an integral part of the locomotor coordination machinery, the development of their electrophysiological character is dependent on vesicular inhibitory amino acid transporter-mediated signaling. Further, Renshaw Cell signaling is closely associated with the molding of motor neuron character proposing the existence of a concerted maturation process, which seems to endow this particular spinal cord circuit with the plasticity to compensate for loss of the Renshaw Cell in adult circuit function.
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Developmental Disruption of Recurrent Inhibitory Feedback Results in Compensatory Adaptation in the Renshaw Cell–Motor Neuron Circuit
The Journal of Neuroscience, 2017Co-Authors: Anders Enjin, Sharn Perry, Markus M Hilscher, Chetan Nagaraja, Martin Larhammar, Henrik Gezelius, Anders Eriksson, Katarina E Leao, Klas KullanderAbstract: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. SIGNIFICANCE STATEMENT We here provide a deeper understanding of spinal cord circuit formation and the repercussions for the possible role for Renshaw Cells in speed and force control. Our results suggest that while Renshaw Cells are not directly required as an integral part of the locomotor coordination machinery, the development of their electrophysiological character is dependent on vesicular inhibitory amino acid transporter-mediated signaling. Further, Renshaw Cell signaling is closely associated with the molding of motor neuron character proposing the existence of a concerted maturation process, which seems to endow this particular spinal cord circuit with the plasticity to compensate for loss of the Renshaw Cell in adult circuit function.
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alterations in the motor neuron Renshaw Cell circuit in the sod1g93a mouse model
The Journal of Comparative Neurology, 2013Co-Authors: Hanna Wootz, Anders Enjin, Martin Larhammar, Klas Kullander, Eileen Fitzsimonskantamneni, Travis M Rotterman, Kalicharan Patra, Elodie Andre, Brigitte Van Zundert, Francisco J AlvarezAbstract:: Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw Cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw Cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these Cells during disease progression in the Sod1(G93A) mouse model. Most calbindin-immunoreactive (IR) Renshaw Cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw Cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw Cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw Cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing. J. Comp. Neurol. 521:1449-1469, 2013. © 2012 Wiley Periodicals, Inc.
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development of spinal motor circuits in the absence of viaat mediated Renshaw Cell signaling
2011Co-Authors: Anders Enjin, Chetan Nagaraja, Martin Larhammar, Henrik Gezelius, Anders Eriksson, Katarina E Leao, Boris Lamotte Dincamps, Klas KullanderAbstract:Movement is central for life, and all animals depend on accurate regulation of movement for purposeful behavior. There is great diversity of movements, ranging between simple and vital breathing movements to minute and subtle movements of the face used to communicate emotions. Consequently, motor neurons, which are the only route of central nervous system output, are essential for all motor behaviors. To control the many motor behaviors expressed by an animal, motor neurons are exposed to a large number and variety of modulating synaptic inputs and have evolved into subtypes with specific functions. In this thesis, motor neuron subtypes and the synaptic input to motor neurons from Renshaw Cells and Ia afferents have been studied. Novel molecular markers that identify subtypes of motor neurons are described. Three markers, Chodl, Calca and ERRβ, have been used to study the degeneration of subtypes of motor neurons in a mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Another marker, 5-ht1d, has been used to record the electrophysiological character of gamma motor neurons. In mice that lack 5-ht1d, motor neurons develop with reduced proprioceptive input. Remarkably, these mice had fewer foot faults than control animals when challenged to cross a narrow beam suggesting that the amplitude of monosynaptic proprioceptive input to motor neurons is not essential for motor coordination. In a final set of experiments, genetic removal of vesicular transport of neurotransmitter from Renshaw Cells suggest that Renshaw Cells are not integral for motor circuit function or motor behaviors. However, they are involved in the development of motor circuits in the spinal cord. Together, this thesis provides novel molecular tools for studies of motor neuron subtypes and novel data regarding the development and function of spinal motor circuits.
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conditional genetic labeling of the Renshaw Cell population for functional studies of motor control
2009Co-Authors: Henrik Gezelius, Anders Enjin, Chetan Nagaraja, Martin Larhammar, Christiane Peuckert, Dominik Langer, Fritjof Helmchen, Klas KullanderAbstract:The Renshaw Cells were among the first interneurons to be characterized in the mammalian spinal cord. Although the basic function of recurrent inhibition to motor neurons, as well as the Renshaw ce ...