Nikolai Chub - Academia.edu (original) (raw)

Papers by Nikolai Chub

Research paper thumbnail of Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons

Human molecular genetics, 2013

The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane prote... more The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) mice that heterologously express human wild-type (WT) and P56S VAPB under the control of a pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein e...

Research paper thumbnail of NKCC1 and AE3 appear to accumulate chloride in embryonic motoneurons

Journal of neurophysiology, 2009

During early development, gamma-aminobutyric acid (GABA) depolarizes and excites neurons, contrar... more During early development, gamma-aminobutyric acid (GABA) depolarizes and excites neurons, contrary to its typical function in the mature nervous system. As a result, developing networks are hyperexcitable and experience a spontaneous network activity that is important for several aspects of development. GABA is depolarizing because chloride is accumulated beyond its passive distribution in these developing cells. Identifying all of the transporters that accumulate chloride in immature neurons has been elusive and it is unknown whether chloride levels are different at synaptic and extrasynaptic locations. We have therefore assessed intracellular chloride levels specifically at synaptic locations in embryonic motoneurons by measuring the GABAergic reversal potential (EGABA) for GABAA miniature postsynaptic currents. When whole cell patch solutions contained 17-52 mM chloride, we found that synaptic EGABA was around -30 mV. Because of the low HCO3- permeability of the GABAA receptor, t...

Research paper thumbnail of GABAergic Synaptic Scaling in Embryonic Motoneurons Is Mediated by a Shift in the Chloride Reversal Potential

Journal of Neuroscience, 2010

Homeostatic synaptic plasticity ensures that networks maintain specific levels of activity by reg... more Homeostatic synaptic plasticity ensures that networks maintain specific levels of activity by regulating synaptic strength in a compensatory manner. When spontaneous network activity (SNA) was blocked in vivo in the embryonic spinal cord, compensatory increases in excitatory GABAergic synaptic inputs were observed. This homeostatic synaptic strengthening was observed as an increase in the amplitude of GABAergic miniature postsynaptic currents (mPSCs). We find that this process is mediated by an increase in chloride accumulation which produces a depolarizing shift in the GABAergic reversal potential (E GABA ). The findings demonstrate a previously unrecognized mechanism underlying homeostatic synaptic scaling. Similar shifts in E GABA have been described following various forms of neuronal injury, introducing the possibility that these shifts in E GABA represent a homeostatic response.

Research paper thumbnail of Imaging the spatiotemporal organization of neural activity in the developing spinal cord

Developmental Neurobiology, 2008

In this review, we discuss the use of imaging to visualize the spatiotemporal organization of net... more In this review, we discuss the use of imaging to visualize the spatiotemporal organization of network activity in the developing spinal cord of the chick embryo and the neonatal mouse. We describe several different methods for loading ionand voltage-sensitive dyes into spinal neurons and consider the advantages and limitations of each one. We review work in the chick embryo, suggesting that motoneurons play a critical role in the initiation of each cycle of spontaneous network activity and describe how imaging has been used to identify a class of spinal interneuron that appears to be the avian homolog of mammalian Renshaw cells or 1a-inhibitory interneurons. Imaging of locomotor-like activity in the neonatal mouse revealed a wave-like activation of motoneurons during each cycle of discharge. We discuss the significance of this finding and its implications for understanding how locomotor-like activity is coordinated across different segments of the cord. In the last part of the review, we discuss some of the exciting new prospects for the future. '

Research paper thumbnail of Mechanisms of Spontaneous Activity in the Developing Spinal Cord and Their Relevance to Locomotion

Annals of the New York Academy of Sciences, 1998

The isolated lumbosacral cord of the chick embryo generates spontaneous episodes of rhythmic acti... more The isolated lumbosacral cord of the chick embryo generates spontaneous episodes of rhythmic activity. Muscle nerve recordings show that the discharge of sartorius (flexor) and femorotibialis (extensor) motoneurons alternates even though the motoneurons are depolarized simultaneously during each cycle. The alternation occurs because sartorius motoneuron firing is shunted or voltage-clamped by its synaptic drive at the time of peak femorotibialis discharge. Ablation experiments have identified a region dorsomedial to the lateral motor column that may be required for the alternation of sartorius and femorotibialis motoneurons. This region overlaps the location of interneurons activated by ventral root stimulation. Wholecell recordings from interneurons receiving short latency ventral root input indicate that they fire at an appropriate time to contribute to the cyclical pause in firing of sartorius motoneurons. Spontaneous activity was modeled by the interaction of three variables: network activity and two activity-dependent forms of network depression. A "slow" depression which regulates the occurrence of episodes and a "fast" depression that controls cycling during an episode. The model successfully predicts several aspects of spinal network behavior including spontaneous rhythmic activity and the recovery of network activity following blockade of excitatory synaptic transmission.

Research paper thumbnail of Mechanisms of excitation of spinal networks by stimulation of the ventral roots

Annals of the New York Academy of Sciences, 2010

It has recently been demonstrated that motoneurons in neonatal rodents release an excitatory amin... more It has recently been demonstrated that motoneurons in neonatal rodents release an excitatory amino acid, in addition to acetylcholine, from their central terminals onto Renshaw cells. Although the function of this amino acid release is not understood, it may mediate the excitatory actions of motor axon stimulation on spinal motor networks. Stimulation of motor axons in the ventral roots or muscle nerves can activate the locomotor central pattern generator or entrain bursting in the disinhibited cord. Both of these effects persist in the presence of cholinergic antagonists and are abolished or diminished by ionotropic and metabotropic glutamate antagonists.

Research paper thumbnail of Neonatal Mouse Spinal Cord Network Activity Generated by the Disinhibited Excitatory Actions of Ventral Root Stimulation During Wan- Wan

You might find this additional info useful... 34 articles, 26 of which can be accessed free at: T... more You might find this additional info useful... 34 articles, 26 of which can be accessed free at: This article cites /content/101/6/2995.full.html#ref-list-1 3 other HighWire hosted articles This article has been cited by [PDF] [Full Text] [Abstract] , December 15, 2012; 108 (12): 3370-3381. J Neurophysiol neonatal mouse Dopamine exerts activation-dependent modulation of spinal locomotor circuits in the [PDF] [Full Text] [Abstract] , June 13, 2013; . Hum. Mol. Genet. function and survival of corticospinal and spinal motor neurons Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the [PDF] [Full Text] [Abstract] , November 1, 2013; 22 (21): 4293-4305. Hum. Mol. Genet.

Research paper thumbnail of Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons

Human molecular genetics, 2013

The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane prote... more The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) mice that heterologously express human wild-type (WT) and P56S VAPB under the control of a pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein e...

Research paper thumbnail of NKCC1 and AE3 appear to accumulate chloride in embryonic motoneurons

Journal of neurophysiology, 2009

During early development, gamma-aminobutyric acid (GABA) depolarizes and excites neurons, contrar... more During early development, gamma-aminobutyric acid (GABA) depolarizes and excites neurons, contrary to its typical function in the mature nervous system. As a result, developing networks are hyperexcitable and experience a spontaneous network activity that is important for several aspects of development. GABA is depolarizing because chloride is accumulated beyond its passive distribution in these developing cells. Identifying all of the transporters that accumulate chloride in immature neurons has been elusive and it is unknown whether chloride levels are different at synaptic and extrasynaptic locations. We have therefore assessed intracellular chloride levels specifically at synaptic locations in embryonic motoneurons by measuring the GABAergic reversal potential (EGABA) for GABAA miniature postsynaptic currents. When whole cell patch solutions contained 17-52 mM chloride, we found that synaptic EGABA was around -30 mV. Because of the low HCO3- permeability of the GABAA receptor, t...

Research paper thumbnail of GABAergic Synaptic Scaling in Embryonic Motoneurons Is Mediated by a Shift in the Chloride Reversal Potential

Journal of Neuroscience, 2010

Homeostatic synaptic plasticity ensures that networks maintain specific levels of activity by reg... more Homeostatic synaptic plasticity ensures that networks maintain specific levels of activity by regulating synaptic strength in a compensatory manner. When spontaneous network activity (SNA) was blocked in vivo in the embryonic spinal cord, compensatory increases in excitatory GABAergic synaptic inputs were observed. This homeostatic synaptic strengthening was observed as an increase in the amplitude of GABAergic miniature postsynaptic currents (mPSCs). We find that this process is mediated by an increase in chloride accumulation which produces a depolarizing shift in the GABAergic reversal potential (E GABA ). The findings demonstrate a previously unrecognized mechanism underlying homeostatic synaptic scaling. Similar shifts in E GABA have been described following various forms of neuronal injury, introducing the possibility that these shifts in E GABA represent a homeostatic response.

Research paper thumbnail of Imaging the spatiotemporal organization of neural activity in the developing spinal cord

Developmental Neurobiology, 2008

In this review, we discuss the use of imaging to visualize the spatiotemporal organization of net... more In this review, we discuss the use of imaging to visualize the spatiotemporal organization of network activity in the developing spinal cord of the chick embryo and the neonatal mouse. We describe several different methods for loading ionand voltage-sensitive dyes into spinal neurons and consider the advantages and limitations of each one. We review work in the chick embryo, suggesting that motoneurons play a critical role in the initiation of each cycle of spontaneous network activity and describe how imaging has been used to identify a class of spinal interneuron that appears to be the avian homolog of mammalian Renshaw cells or 1a-inhibitory interneurons. Imaging of locomotor-like activity in the neonatal mouse revealed a wave-like activation of motoneurons during each cycle of discharge. We discuss the significance of this finding and its implications for understanding how locomotor-like activity is coordinated across different segments of the cord. In the last part of the review, we discuss some of the exciting new prospects for the future. '

Research paper thumbnail of Mechanisms of Spontaneous Activity in the Developing Spinal Cord and Their Relevance to Locomotion

Annals of the New York Academy of Sciences, 1998

The isolated lumbosacral cord of the chick embryo generates spontaneous episodes of rhythmic acti... more The isolated lumbosacral cord of the chick embryo generates spontaneous episodes of rhythmic activity. Muscle nerve recordings show that the discharge of sartorius (flexor) and femorotibialis (extensor) motoneurons alternates even though the motoneurons are depolarized simultaneously during each cycle. The alternation occurs because sartorius motoneuron firing is shunted or voltage-clamped by its synaptic drive at the time of peak femorotibialis discharge. Ablation experiments have identified a region dorsomedial to the lateral motor column that may be required for the alternation of sartorius and femorotibialis motoneurons. This region overlaps the location of interneurons activated by ventral root stimulation. Wholecell recordings from interneurons receiving short latency ventral root input indicate that they fire at an appropriate time to contribute to the cyclical pause in firing of sartorius motoneurons. Spontaneous activity was modeled by the interaction of three variables: network activity and two activity-dependent forms of network depression. A "slow" depression which regulates the occurrence of episodes and a "fast" depression that controls cycling during an episode. The model successfully predicts several aspects of spinal network behavior including spontaneous rhythmic activity and the recovery of network activity following blockade of excitatory synaptic transmission.

Research paper thumbnail of Mechanisms of excitation of spinal networks by stimulation of the ventral roots

Annals of the New York Academy of Sciences, 2010

It has recently been demonstrated that motoneurons in neonatal rodents release an excitatory amin... more It has recently been demonstrated that motoneurons in neonatal rodents release an excitatory amino acid, in addition to acetylcholine, from their central terminals onto Renshaw cells. Although the function of this amino acid release is not understood, it may mediate the excitatory actions of motor axon stimulation on spinal motor networks. Stimulation of motor axons in the ventral roots or muscle nerves can activate the locomotor central pattern generator or entrain bursting in the disinhibited cord. Both of these effects persist in the presence of cholinergic antagonists and are abolished or diminished by ionotropic and metabotropic glutamate antagonists.

Research paper thumbnail of Neonatal Mouse Spinal Cord Network Activity Generated by the Disinhibited Excitatory Actions of Ventral Root Stimulation During Wan- Wan

You might find this additional info useful... 34 articles, 26 of which can be accessed free at: T... more You might find this additional info useful... 34 articles, 26 of which can be accessed free at: This article cites /content/101/6/2995.full.html#ref-list-1 3 other HighWire hosted articles This article has been cited by [PDF] [Full Text] [Abstract] , December 15, 2012; 108 (12): 3370-3381. J Neurophysiol neonatal mouse Dopamine exerts activation-dependent modulation of spinal locomotor circuits in the [PDF] [Full Text] [Abstract] , June 13, 2013; . Hum. Mol. Genet. function and survival of corticospinal and spinal motor neurons Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the [PDF] [Full Text] [Abstract] , November 1, 2013; 22 (21): 4293-4305. Hum. Mol. Genet.