Inducing Chronic Excitotoxicity in the Mouse Spinal Cord to Investigate Lower Motor Neuron Degeneration

Blizzard, CL; Lee, K. M.; Dickson, Tracey C.

doi:10.3389/fnins.2016.00076

Cited by 13 publications

(7 citation statements)

References 41 publications

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“…For analysis of cortical interneuron pathology, free-floating sections were processed using standard immunohistochemical methods 57 78 . Cortical interneurons were identified by the expression of calcium binding proteins: calbindin (CB), calretinin (CR) and parvalbumin (PV), or by neuropeptides: neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and somatostatin (SOM) 19 .…”

Section: Methodsmentioning

confidence: 99%

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS

Clark

Blizzard

Young

et al. 2017

Sci Rep

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Increasing evidence indicates an excitatory/inhibitory imbalance may have a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Impaired inhibitory circuitry is consistently reported in the motor cortex of both familial and sporadic patients, closely associated with cortical hyperexcitability and ALS onset. Inhibitory network dysfunction is presumably mediated by intra-cortical inhibitory interneurons, however, the exact cell types responsible are yet to be identified. In this study we demonstrate dynamic changes in the number of calretinin- (CR) and neuropeptide Y-expressing (NPY) interneurons in the motor cortex of the familial hSOD1G93A ALS mouse model, suggesting their potential involvement in motor neuron circuitry defects. We show that the density of NPY-populations is significantly decreased by ~17% at symptom onset (8 weeks), and by end-stage disease (20 weeks) is significantly increased by ~30%. Conversely, the density of CR-populations is progressively reduced during later symptomatic stages (~31%) to end-stage (~36%), while CR-expressing interneurons also show alteration of neurite branching patterns at symptom onset. We conclude that a differential capacity for interneurons exists in the ALS motor cortex, which may not be a static phenomenon, but involves early dynamic changes throughout disease, implicating specific inhibitory circuitry.

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Section: Methodsmentioning

confidence: 99%

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS

Clark

Blizzard

Young

et al. 2017

Sci Rep

Self Cite

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“…Using a scalpel, a skin incision was made over the T12-L3 vertebrae. Small scissors were used to cut through fascia, and #5 forceps were used to separate muscle from the T12-T13 vertebrae, exposing the intervertebral space above the left L3/L4 spinal segments [10,23]. Laminectomies were avoided to minimize spinal cord trauma.…”

Section: Intraspinal Viral Injectionsmentioning

confidence: 99%

The Neurokinin-1 Receptor is Expressed with Gastrin-Releasing Peptide Receptor in Spinal Interneurons and Modulates Itch

et al. 2020

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The neurokinin-1 receptor (NK1R, encoded by Tacr1) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. Thus, we leveraged a newly developed Tacr1 CreER mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of Tacr1 CreER spinal neurons increases itch behavior, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence in situ hybridization to characterize the endogenous expression of Tacr1 throughout the superficial and deeper dorsal horn, as well as the lateral spinal nucleus. Retrograde labeling studies from the parabrachial nucleus show that less than 20% of superficial Tacr1 CreER dorsal horn neurons are spinal projection neurons, and thus the majority of Tacr1 CreER are local interneurons. We then use a combination of in situ hybridization and ex vivo two-photon Ca 2+ imaging of the spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn neurons. These findings are the first to describe a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry..

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“…Furthermore, the toxicity conveyed by the CSF from ALS patients could be prevented by the application of AMPA and kainate receptor antagonists in cell culture (Couratier et al, 1993;Sen et al, 2005). Chronic delivery of 3 and 5 mM kainic acid (kainate and AMPA receptor agonist) via intrathecal pumps for 4 weeks resulted in MN death in the spinal cord of mice and rats (Sun et al, 2006;Blizzard et al, 2016). While the latter experiments seem to support the glutamatemediated excitotoxicity hypothesis, it is important to realize that the concentrations applied are two orders of magnitude higher than the glutamate levels observed in the CSF of ALS patients.…”

Section: Glutamate-mediated Excitotoxicitymentioning

confidence: 99%

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

Gunes

Kan

et al. 2020

Front. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a muchimproved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell typespecific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area-and disease stage-specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.

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Inducing Chronic Excitotoxicity in the Mouse Spinal Cord to Investigate Lower Motor Neuron Degeneration

Cited by 13 publications

References 41 publications

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS

Calretinin and Neuropeptide Y interneurons are differentially altered in the motor cortex of the SOD1G93A mouse model of ALS

The Neurokinin-1 Receptor is Expressed with Gastrin-Releasing Peptide Receptor in Spinal Interneurons and Modulates Itch

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

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