Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

In an effort to find possible new gene candidates involved in the causation of amyotrophic lateral sclerosis (ALS), a prior version of the on-line brain gene expression atlas GENSAT was extensively searched for selectively intense expression within spinal motor neurons. Using autoradiographic data of in-situ hybridization from 3430 genes, a search for selectively intense activity was made for the anterior horn region of murine lumbar spinal cord sectioned in the axial plane. Of 3430 genes, a group of 17 genes was found to be highly expressed within the anterior horn suggesting localization to its primary cellular constituent, the alpha spinal motor neuron. For some genes, an inter-relationship to ALS was already known, such as for heavy, medium, and light neurofilaments, and peripherin. Other genes identified include: Gamma Synuclein, GDNF, SEMA3A, Extended Synaptotagmin-like protein 1, LYNX1, HSPA12a, Cadherin 22, PRKACA, TPPP3 as well as Choline Acetyltransferase, Janus Kinase 1, and the Motor Neuron and Pancreas Homeobox 1. Based on this study, Fibroblast Growth Factor 1 was found to have a particularly selective and intense localization pattern to the ventral horn and may be a good target for development of motor neuron disease therapies; further research is needed.

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Rodent Experimental Model of Konzo: Characterization of Motor Impairment and Neurodegeneration after Cassava Neurotoxicity in the Rat

NIgerian Journal of Neuroscience ◽

10.47081/njn2021.12.1/001 ◽

2021 ◽

Vol 12 (1) ◽

pp. 1-13

Author(s):

Lekpa David ◽

◽

Chikwuogwo Paul ◽

Peace Chigeru ◽

John Martin ◽

...

Keyword(s):

Spinal Cord ◽

Motor Cortex ◽

Motor Neuron ◽

Success Rate ◽

Structural Changes ◽

Spastic Paraparesis ◽

Ventral Horn ◽

Reach To Grasp ◽

Significant Difference ◽

Bitter Cassava

Konzo is a motor neuron neurodegenerative disease caused by bitter cassava toxicity that presents as a non-progressive spastic paraparesis. The ability of bitter cassava to produce behavioural and structural changes in adult rat nervous system was examined. Twenty five rats were used for this study, and pruned to 20 after consistent baseline performance was achieved (n=20; control=5, cassava chow=15). The rats were switched to a cassava diet for another 5 weeks (n=15). After the cassava consumption period, 5 rats underwent rehabilitation training three times a week and their performance tested once in a week for 5 weeks. Quantitative and qualitative assessments using a reaching movement scale and reach-to-grasp success rate were respectively carried out. Animals subjected to cassava toxicity performed significantly worse than the controls when determining the success rate in a reach-to-grasp experiment (baseline=69.8%, cassava diet=21.4%, post-cassava diet =48.9%). The various movement of the rat was analysed using ANOVA and there was significant difference (p < 0.05) in the performance. The rats couldn’t pronate, grasp, withdraw or open the digits properly when fed with cassava diet. Histology showed neuropathological damages on the motor cortex, less neurons in the motor neuron pool of the spinal cord and disruption of pyramidal layer of the hippocampus when rats were given bitter cassava. Immunofluorescence stain shows motor neurons and numerous choline acetyltransferase (ChAT+) processes and some C-boutons. There are behavioural evidence and neuropathological changes in the motor cortex and ventral horn of the spinal cord that may underlie movement impairments in rats fed with bitter cassava.

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Intrathecal Magnesium Sulfate Administration at the Time of Experimental Ischemia Improves Neurological Functioning by Reducing Acute and Delayed Loss of Motor Neurons in the Spinal Cord

Anesthesiology ◽

10.1097/01.anes.0000296109.04010.82 ◽

2008 ◽

Vol 108 (1) ◽

pp. 78-86 ◽

Cited By ~ 15

Author(s):

Walter S. Jellish ◽

Xin Zhang ◽

Kenneth E. Langen ◽

Matthew S. Spector ◽

Michael T. Scalfani ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Magnesium Sulfate ◽

Motor Function ◽

Neuronal Degeneration ◽

Spinal Cord Ischemia ◽

Recovery Period ◽

Neuronal Loss ◽

Ventral Horn ◽

Lower Lumbar

Background In this study, the authors determined the effect of magnesium sulfate on intrathecal glutamate concentrations, hindlimb motor function, and histopathology after a transient episode of spinal cord ischemia. Methods Fifty-two New Zealand White rabbits underwent spinal cord ischemia for 30 min. Fifteen minutes before ischemia, animals received intrathecal magnesium sulfate (MgSO4) (3 mg/kg) or placebo (artificial cerebrospinal fluid). Intrathecal microdialysis samples were measured for glutamate using high-performance liquid chromatography. Neurologic function and spinal cord histopathology were assessed throughout the recovery period. Results Intrathecal glutamate levels in placebo-treated animals were higher after spinal cord ischemia compared with sham- and MgSO4-treated animals. MgSO4-treated animals had increased lower extremity motor function compared with the placebo group (64.7% vs 14.3%, P < 0.01). Histologic examination of placebo-treated animals revealed significant motor neuron cell loss at thoracolumbar levels by Day 7 (P < 0.05), whereas lower lumbar regions displayed significant neuron loss on Day 1. Spinal cords from MgSO4-treated animals exhibited less neuronal loss in lumbar regions. Similar effects were present in the thoracolumbar segments on Day 7. A significant correlation existed between diminished neuronal loss and hind leg movement (Tarlov score) and demonstrates that the neurologic outcome after MgSO4 treatment was related to lower lumbar ventral horn cell survival (r2 = 0.812, P < 0.001). Conclusions These results demonstrate that MgSO4 affords significant spinal cord motor neuron protection by diminishing acute neuronal loss at the foci of the ischemic injury (L3-L6) with delayed neuronal degeneration in adjacent spinal cord regions (T7-L2).

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Protein Aggregation and Defective RNA Metabolism as Mechanisms for Motor Neuron Damage

CNS & Neurological Disorders - Drug Targets ◽

10.2174/187152710791292585 ◽

2010 ◽

Vol 9 (3) ◽

pp. 285-296 ◽

Cited By ~ 28

Author(s):

N. Ticozzi ◽

A. Ratti ◽

V. Silani

Keyword(s):

Protein Aggregation ◽

Motor Neuron ◽

Rna Metabolism ◽

Neuron Damage ◽

Defective Rna

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Distribution of substance P in the spinal cord of patients with syringomyelia

Journal of Neurosurgery ◽

10.3171/jns.1996.84.6.0992 ◽

1996 ◽

Vol 84 (6) ◽

pp. 992-998 ◽

Cited By ~ 10

Author(s):

Thomas H. Milhorat ◽

Harrison T. M. Mu ◽

Carole C. LaMotte ◽

Ade T. Milhorat

Keyword(s):

Spinal Cord ◽

Substance P ◽

Dorsal Horn ◽

Ventral Horn ◽

Immunohistochemical Method ◽

Positive Staining ◽

Content Type ◽

Normal Individuals ◽

Neurologically Normal ◽

Intermediolateral Nucleus

✓ The distribution of substance P, a putative neurotransmitter and pain-related peptide, was studied using the peroxidase—antiperoxidase immunohistochemical method in the spinal cords obtained from autopsy of 10 patients with syringomyelia and 10 age- and sex-matched, neurologically normal individuals. Substance P immunoreactivity was present in axons and in terminal-like processes in close apposition to neurons in the first, second, and third laminae of the dorsal horn. Smaller amounts of peroxidase-positive staining were found in the fifth lamina of the dorsal horn, the intermediolateral nucleus, the intermediomedial nucleus, and the ventral horn. In nine of 10 patients with syringomyelia, there was a substantial increase in substance P immunoreactivity in the first, second, third, and fifth laminae below the level of the lesion. A marked reduction or absence of staining was present in segments of the spinal cord occupied by the syrinx. Central cavities produced bilateral abnormalities, whereas eccentric cavities produced changes that were ipsilateral to the lesion. No alterations in staining were found in the spinal cord of an asymptomatic patient with a small central syrinx. The authors conclude that syringomyelia can be associated with abnormalities in spinal cord levels of substance P, which may affect the modulation and perception of pain.

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Red nucleus projections to distinct motor neuron pools in the rat spinal cord

The Journal of Comparative Neurology ◽

10.1002/cne.10259 ◽

2002 ◽

Vol 448 (4) ◽

pp. 349-359 ◽

Cited By ~ 95

Author(s):

Martin Küchler ◽

Karim Fouad ◽

Oliver Weinmann ◽

Martin E. Schwab ◽

Olivier Raineteau

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Red Nucleus ◽

Rat Spinal Cord

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Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signaling

Journal of Neurophysiology ◽

10.1152/jn.00783.2017 ◽

2018 ◽

Vol 120 (3) ◽

pp. 998-1009 ◽

Cited By ~ 10

Author(s):

David Acton ◽

Matthew J. Broadhead ◽

Gareth B. Miles

Keyword(s):

Spinal Cord ◽

Protein Kinase ◽

Dopamine Receptor ◽

Kinase Inhibitor ◽

Ventral Horn ◽

Skf 38393 ◽

Network Activity ◽

Related Activity ◽

Burst Frequency ◽

Spinal Motor

Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output. NEW & NOTEWORTHY Astrocytes within the spinal cord produce adenosine during ongoing locomotor-related activity or when experimentally stimulated. Here, we show that adenosine derived from astrocytes acts at A1 receptors to inhibit a pathway by which D1-like receptors enhance the frequency of locomotor-related bursting. These data support a novel form of metamodulation within the mammalian spinal cord, enhancing our understanding of neuron-astrocyte interactions and their importance in shaping network activity.

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