Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders

Zhang, Wen; Zhang, Lifeng; Liang, Bo; Schroeder, David G.; Zhang, Zhong Wei; Cox, Gregory A.; Li, Yun; Lin, Da-Ting

doi:10.1038/nn.4257

Cited by 135 publications

(147 citation statements)

References 30 publications

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“…Specifically, we found that SST + interneurons were present at various levels of maturity at D54. SST cell death has been observed in mood disorders and dysfunctional SST interneurons have recently been shown to exacerbate cortical excitotoxicity in neurodegenerative disorders (Lin and Sibille, 2013;Zhang et al, 2016). Our analysis determined that several genes important for migration, synaptogenesis, axon outgrowth and ion channel function were differentially expressed by more mature interneurons.…”

Section: Discussionmentioning

confidence: 80%

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Close¹,

Yao²,

Miller³

et al. 2017

Neuron

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SummaryGABAergic interneurons are essential for neural circuit function and their loss or dysfunction is implicated in human neuropsychiatric disease. In vitro methods for interneuron generation hold promise for studying human cellular and functional properties and ultimately therapeutic cell replacement. We describe here a protocol for generating cortical interneurons from hESCs and analyze the properties and maturation timecourse of cell types using single-cell RNAseq. We find that the cell types produced mimic in vivo temporal patterns of neuron and glial production, with immature progenitors and neurons observed early and mature cortical neurons and glial cell types produced late. By comparing the transcriptomes of immature interneurons to more mature neurons, we identified genes important for human interneuron differentiation. Many of these genes were previously implicated in neurodevelopmental and neuropsychiatric disorders. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access

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Section: Discussionmentioning

confidence: 80%

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Close¹,

Yao²,

Miller³

et al. 2017

Neuron

View full text Add to dashboard Cite

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“…In asymptomatic mutation carriers, SICI appears to be within normal limits, indicative of a normal level of cortical excitability [89,92], and suggesting that factors other than the inheritance of the genetic mutation are important to trigger the disease. Degeneration of inhibitory cortical interneurons along with hyperactivity of cortical excitatory interneurons appears to underlie the reduction of SICI and enhancement of ICF in ALS [94,95]. Given that seizures can affect TMS parameters [96], patients with ALS with seizure disorders were excluded from the above-discussed studies.…”

Section: Alsmentioning

confidence: 99%

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Vucic

Kiernan

2017

Neurotherapeutics

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Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motorevoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.

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“…Excess extracellular glutamate causes neuronal death by the disruption of intracellular organelles and aberrant proteolysis via ion-sensitive protease activation that results from excessive Ca 2ϩ influx following the overstimulation of Ca 2ϩ -permeable glutamate receptors (Hollmann et al, 1991;Verdoorn et al, 1991;Bano et al, 2005;Kwak and Weiss, 2006;Lewerenz and Maher, 2015). Accumulating evidence implicates excitotoxicity involvement in the pathogenesis of many neurodegenerative diseases including Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS; Kawahara et al, 2004;Kwak and Weiss, 2006;Mehta et al, 2013;Zhang et al, 2016), suggesting that these diseases may share excitotoxicity as a common pathogenic pathway. Thus, understanding the molecular mechanisms underlying chronic excitotoxic neuronal death is of critical importance for the treatment of many neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

et al. 2017

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Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many neurodegenerative diseases. In the case of motor neuron disease, there is significant evidence to suggest that the overactivation of AMPA receptors due to deficiencies in the expression and function of glial glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST(+/-)/GLT1-cKO). GLAST(+/-)/GLT1-cKO mice (both sexes) exhibited nuclear irregularity and calpain-mediated degradation of nuclear pore complexes (NPCs), which are responsible for nucleocytoplasmic transport. These abnormalities were associated with progressive motor neuron loss, severe paralysis, and shortened lifespan. The nuclear export inhibitor KPT-350 slowed but did not prevent motor neuron death, whereas long-term treatment of the AMPA receptor antagonist perampanel and the calpain inhibitor SNJ-1945 had more persistent beneficial effects. Thus, NPC degradation contributes to AMPA receptor-mediated excitotoxic motor neuronal death, and preventing NPC degradation has robust protective effects. Normalization of NPC function could be a novel therapeutic strategy for neurodegenerative disorders in which AMPA receptor-mediated excitotoxicity is a contributory factor.SIGNIFICANCE STATEMENT Despite glial glutamate transporter dysfunction leading to excitotoxicity has been documented in many neurological diseases, it remains unclear whether its dysfunction is a primary cause or secondary outcome of neuronal death at disease state. Here we show the combined loss of glial glutamate transporters GLT1 and GLAST in spinal cord caused motor neuronal death and hindlimb paralysis. Further, our novel mutant exhibits the nuclear irregularities and calpain-mediated progressive nuclear pore complex degradation. Our study reveals that glial glutamate transporter dysfunction is sufficient to cause motor neuronal death in vivo. Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many neurodegenerative diseases. In the case of motor neuron disease, there is significant evidence to suggest that the overactivation of AMPA receptors due to deficiencies in the expression and function of glial glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST ϩ/Ϫ /GLT1-cKO). GLAST ϩ/Ϫ /G...

show abstract

Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders

Cited by 135 publications

References 30 publications

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

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