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

Clark, Rosemary M.; Blizzard, CL; Young, Karen; King, Anna E.; Dickson, Tracey C.

doi:10.1038/srep44461

Cited by 39 publications

(38 citation statements)

References 80 publications

(110 reference statements)

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“…Although compromised nonmotor neurons have not been formally shown to cause motor function loss in ALS, it has been suggested that neurodegenerative disorders can arise from circuit or network disorders (Warren et al, 2013;Fornito et al, 2015). Certainly, in late-stage ALS, disruptions in interneuron and/or sensory function were found to accompany severe motor deficits (Theys et al, 1999;Fischer et al, 2005;Stephens et al, 2006;Isaacs et al, 2007;Pugdahl et al, 2007;Sunico et al, 2011;McGown et al, 2013;Vinsant et al, 2013;Vaughan et al, 2015;Clark et al, 2017). Interestingly, in several models of ALS, an observed locomotor defect is associated with only a minor decrease in NMJ transmission (Diaper et al, 2013;Rocha et al, 2013;Zhang et al, 2015), one that would not have been expected to overcome the large safety factor observed at NMJs (Marrus and DiAntonio, 2005).…”

Section: Motor Circuit Dysfunction Results In Locomotor Defects In a mentioning

confidence: 99%

Circuit Dysfunction inSOD1-ALSModel First Detected in Sensory Feedback Prior to Motor Neuron Degeneration Is Alleviated by BMP Signaling

Held

Major²,

Şahin³

et al. 2019

J. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which the origin and underlying cellular defects are not fully understood. Although motor neuron degeneration is the signature feature of ALS, it is not clear whether motor neurons or other cells of the motor circuit are the site of disease initiation. To better understand the contribution of multiple cell types in ALS, we made use of a Drosophila Sod1 G85R knock-in model, in which all cells harbor the disease allele. End-stage dSod1 G85R animals of both sexes exhibit severe motor deficits with clear degeneration of motor neurons. Interestingly, earlier in dSod1 G85R larvae, motor function is also compromised, but their motor neurons exhibit only subtle morphological and electrophysiological changes that are unlikely to cause the observed decrease in locomotion. We analyzed the intact motor circuit and identified a defect in sensory feedback that likely accounts for the altered motor activity of dSod1 G85R. We found cell-autonomous activation of bone morphogenetic protein signaling in proprioceptor sensory neurons which are critical for the relay of the contractile status of muscles back to the central nerve cord, completely rescues early-stage motor defects and partially rescue late-stage motor function to extend lifespan. Identification of a defect in sensory feedback as a potential initiating event in ALS motor dysfunction, coupled with the ability of modified proprioceptors to alleviate such motor deficits, underscores the critical role that nonmotor neurons play in disease progression and highlights their potential as a site to identify early-stage ALS biomarkers and for therapeutic intervention.

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Section: Motor Circuit Dysfunction Results In Locomotor Defects In a mentioning

confidence: 99%

Circuit Dysfunction inSOD1-ALSModel First Detected in Sensory Feedback Prior to Motor Neuron Degeneration Is Alleviated by BMP Signaling

Held

Major²,

Şahin³

et al. 2019

J. Neurosci.

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“…The strong predictive correlations of NPY levels to core diagnostic clinical features in addition to their reflection of eating behavior, supports a role in the underlying pattern of neurodegeneration. In ALS, NPY has been hypothesized to contribute to neuronal activity in the motor cortex of the brain, with ALS mouse models showing decreased NPY interneurons at symptom onset, but increased NPY interneurons by end stage disease . Interneurons are believed to contribute to cortical hyperexcitability, a core feature of ALS pathogenesis .…”

Section: Discussionmentioning

confidence: 99%

Eating peptides: biomarkers of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia

Ahmed

Phan

Highton‐Williamson

et al. 2019

Ann Clin Transl Neurol

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Objective Physiological changes potentially influence disease progression and survival along the Amyotrophic Lateral Sclerosis (ALS)‐Frontotemporal dementia (FTD) spectrum. The peripheral peptides that regulate eating and metabolism may provide diagnostic, metabolic, and progression biomarkers. The current study aimed to examine the relationships and biomarker potential of hormonal peptides. Methods One hundred and twenty‐seven participants (36 ALS, 26 ALS‐ cognitive, patients with additional cognitive behavioral features, and 35 behavioral variant FTD (bvFTD) and 30 controls) underwent fasting blood analyses of leptin, ghrelin, neuropeptide Y (NPY), peptide YY (PYY), and insulin levels. Relationships between endocrine measures, cognition, eating behaviors, and body mass index (BMI) were investigated. Biomarker potential was evaluated using multinomial logistic regression for diagnosis and correlation to disease duration. Results Compared to controls, ALS and ALS‐cognitive had higher NPY levels and bvFTD had lower NPY levels, while leptin levels were increased in all patient groups. All groups had increased insulin levels and a state of insulin resistance compared to controls. Lower NPY levels correlated with increasing eating behavioral change and BMI, while leptin levels correlated with BMI. On multinomial logistic regression, NPY and leptin levels were found to differentiate between diagnosis. Reduced Neuropeptide Y levels correlated with increasing disease duration, suggesting it may be useful as a potential marker of disease progression. Interpretation ALS‐FTD is characterized by changes in NPY and leptin levels that may impact on the underlying regional neurodegeneration as they were predictive of diagnosis and disease duration, offering the potential as biomarkers and for the development of interventional treatments.

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“…TDP-43 and SOD1 ALS rodent models identify changes in the excitability of MNs prior to symptoms (Fogarty et al, 2015 ; Handley et al, 2017 ). However, more recent studies recognize progressive alterations in the number and excitability of interneurons throughout the disease course in TDP-43 and SOD1 models (Zhang et al, 2016 ; Clark et al, 2017 ; Kim et al, 2017 ). Clinical imaging studies indicate loss of inhibitory activity is a common and early feature of cortical hyperexcitability (Menon et al, 2015 ), and a key determinant of clinical disease progression (Shibuya et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Here, we focused on the potential for the familial hSOD1 G93A mutation to influence firing properties and morphology of cortical interneurons in Gad67-GFP::hSOD1 G93A cultures. Structural alteration of pyramidal neurons is demonstrated in hSOD1 G93A studies (Jara et al, 2012 ; Fogarty et al, 2016 ; Saba et al, 2016 ), but few studies report changes to the morphological fine structure of interneurons (Clark et al, 2017 ). Additionally, mutant SOD1 is theorized to mediate non-cell autonomous pathogenicity through perturbed function of multiple cell types early in development (Kuo et al, 2004 ; van Zundert et al, 2008 ; Martin et al, 2013 ; Wainger et al, 2014 ; Devlin et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis

Clark

Brizuela

Blizzard

et al. 2018

Front. Cell. Neurosci.

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Cortical interneurons play a crucial role in regulating inhibitory-excitatory balance in brain circuits, filtering synaptic information and dictating the activity of pyramidal cells through the release of GABA. In the fatal motor neuron (MN) disease, amyotrophic lateral sclerosis (ALS), an imbalance between excitation and inhibition is an early event in the motor cortex, preceding the development of overt clinical symptoms. Patients with both sporadic and familial forms of the disease exhibit reduced cortical inhibition, including patients with mutations in the copper/zinc superoxide-dismutase-1 (SOD1) gene. In this study, we investigated the influence of the familial disease-causing hSOD1-G93A ALS mutation on cortical interneurons in neuronal networks. We performed whole-cell patch-clamp recordings and neurobiotin tracing from GFP positive interneurons in primary cortical cultures derived from Gad67-GFP::hSOD1G93A mouse embryos. Targeted recordings revealed no overt differences in the passive properties of Gad67-GFP::hSOD1G93A interneurons, however the peak outward current was significantly diminished and cells were less excitable compared to Gad67-GFP::WT controls. Post hoc neurite reconstruction identified a significantly increased morphological complexity of the Gad67-GFP::hSOD1G93A interneuron neurite arbor compared to Gad67-GFP::WT controls. Our results from the SOD1 model suggest that cortical interneurons have electrophysiological and morphological alterations that could contribute to attenuated inhibitory function in the disease. Determining if these phenomena are driven by the network or represent intrinsic alteration of the interneuron may help explain the emergence of inhibitory susceptibility and ultimately disrupted excitability, in ALS.

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

Cited by 39 publications

References 80 publications

Circuit Dysfunction inSOD1-ALSModel First Detected in Sensory Feedback Prior to Motor Neuron Degeneration Is Alleviated by BMP Signaling

Circuit Dysfunction inSOD1-ALSModel First Detected in Sensory Feedback Prior to Motor Neuron Degeneration Is Alleviated by BMP Signaling

Eating peptides: biomarkers of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia

Reduced Excitability and Increased Neurite Complexity of Cortical Interneurons in a Familial Mouse Model of Amyotrophic Lateral Sclerosis

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