scholarly journals Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease

2016 ◽  
Author(s):  
KD Girling ◽  
YT Wang
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Cell Survival ◽  
Huntington’S Disease ◽  
Glutamate Release ◽  
Clinical Approach ◽  
Wide Range ◽  
Pubmed Search ◽  
Nmdar Activation ◽  
Cell Death Signaling

AbstractBACKGROUNDHuntington’s Disease (HD) is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors (NMDARs) has been shown to have a key role in the neuropathogenesis of HD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cell-survival activity of GluN2A-NMDARs.OBJECTIVEThis review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target.METHODSA systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 250 articles were consulted for the review, with key search terms including “Huntington’s Disease”, “excitotoxicity”, “NMDAR” and “therapeutics”.RESULTSA wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs.CONCLUSIONThe current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.

scholarly journals Direct assessment of presynaptic modulation of cortico-striatal glutamate release in a Huntington’s disease mouse model

2018 ◽  
Vol 120 (6) ◽  
pp. 3077-3084 ◽  
Author(s):  
Ellen T. Koch ◽  
Cameron L. Woodard ◽  
Lynn A. Raymond
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Frequency ◽  
Glutamate Release ◽  
Presynaptic Receptors ◽  
High Frequency Stimulation ◽  
Presynaptic Modulation ◽  
Frequency Stimulation

Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington’s disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest that glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model. We determined that iGluSnFR can be used to accurately measure short- and long-term changes in glutamate release caused by modulation of extracellular Ca2+ levels, activation of presynaptic receptors, and high-frequency stimulation (HFS) protocols. We also confirmed a difference in the expression of HFS-induced long-term depression in YAC128. Together, this research demonstrates the utility of iGluSnFR in studying presynaptic modulation of glutamate release in healthy mice and disease models that display impairments in glutamate signaling. NEW & NOTEWORTHY We use iGluSnFR to directly assess presynaptic modulation of cortico-striatal glutamate release in brain slice and compare changes in glutamate release between wild type and a Huntington’s disease mouse model, YAC128. We observed reductions in glutamate release after low extracellular Ca2+ and activation of various presynaptic receptors. We also demonstrate a presynaptic mechanism of reduced glutamate release in high-frequency stimulation-induced long-term depression and show this to be altered in YAC128.

Mechanisms of neuronal cell death in Huntington’s disease

2003 ◽  
Vol 100 (1-4) ◽  
pp. 287-295 ◽  
Author(s):  
A. Sawa ◽  
T. Tomoda ◽  
B.-I. Bae
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Cell Death ◽  
Neuronal Cell

scholarly journals Calpain Is a Major Cell Death Effector in Selective Striatal Degeneration InducedIn Vivoby 3-Nitropropionate: Implications for Huntington's Disease

2003 ◽  
Vol 23 (12) ◽  
pp. 5020-5030 ◽  
Author(s):  
Nicolas Bizat ◽  
Jean-Michel Hermel ◽  
Frédéric Boyer ◽  
Carine Jacquard ◽  
Christophe Créminon ◽  
...  
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Striatal Degeneration ◽  
Death Effector

Age-Dependent Biphasic Changes in Ischemic Sensitivity in the Striatum of Huntington's Disease R6/2 Transgenic Mice

2005 ◽  
Vol 93 (2) ◽  
pp. 758-765 ◽  
Author(s):  
Gloria J. Klapstein ◽  
Michael S. Levine
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Glutamate Release ◽  
Age Groups ◽  
Brain Slices ◽  
Glucose Deprivation ◽  
Behavioral Phenotype ◽  
Crossover Point ◽  
Glutamate Receptor Antagonist ◽  
Age Dependent

We used the oxygen/glucose deprivation (OGD) model of ischemia in corticostriatal brain slices to test the hypothesis that metabolic deficiencies in R6/2 transgenic Huntington's disease (HD) mice will impair their recovery from an ischemic challenge. Corticostriatal extracellular field excitatory postsynaptic potentials (fEPSPs) were evoked in transgenic and wild-type (WT) mice in three age groups: 3–4 wk, before the overt behavioral phenotype develops; 5–9 wk, as overt behavioral symptoms begin; and 10–15 wk when symptoms were most severe. OGD for 8 min completely and reversibly inhibited fEPSPs. Although responses of 3–4 wk WTs showed a tolerance to ischemia and recovered rapidly, ischemic sensitivity developed progressively; at 5–9 and 10–15 wk, responses recovered more slowly from OGD. In contrast, although 3–4 wk R6/2 transgenic fEPSPs showed significantly more ischemic sensitivity than their WT counterparts, the R6/2 fEPSPs maintained a relative tolerance to ischemia at 5–9 and 10–15 wk. As a result, a “crossover” point occurred, roughly coinciding with the development of the overt behavioral phenotype (5–9 wk), after which time R6/2 fEPSPs were significantly more resistant to ischemia than WT responses. The increased ischemic sensitivity in 3–4 wk R6/2 responses was not due to excessive glutamate release during OGD as it persisted in the presence of the glutamate receptor antagonist kynurenic acid (1 mM). Although the mechanism for development of ischemic resistance in R6/2 transgenics remains unknown, it correlates with metabolic and biochemical changes described in this model and in HD patients.

scholarly journals Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length

2001 ◽  
Vol 78 (4) ◽  
pp. 694-703 ◽  
Author(s):  
Oskar Hansson ◽  
Roger F. Castilho ◽  
Laura Korhonen ◽  
Dan Lindholm ◽  
Gillian P. Bates ◽  
...  
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Partial Resistance ◽  
Repeat Length ◽  
Cag Repeat ◽  
Transgenic Mouse Models

scholarly journals Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease

2003 ◽  
Vol 100 (18) ◽  
pp. 10483-10487 ◽  
Author(s):  
X. Wang ◽  
S. Zhu ◽  
M. Drozda ◽  
W. Zhang ◽  
I. G. Stavrovskaya ◽  
...  
Keyword(s):  
Cell Death ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Death Pathways

scholarly journals Proteasomal-Dependent Aggregate Reversal and Absence of Cell Death in a Conditional Mouse Model of Huntington's Disease

2001 ◽  
Vol 21 (22) ◽  
pp. 8772-8781 ◽  
Author(s):  
Ester Martı́n-Aparicio ◽  
Ai Yamamoto ◽  
Félix Hernández ◽  
René Hen ◽  
Jesús Avila ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Conditional Mouse Model

Late-Onset Huntington's Disease: A Geriatric Psychiatry Perspective

1996 ◽  
Vol 9 (1) ◽  
pp. 26-29 ◽  
Author(s):  
Kenneth I. Shulman ◽  
Anne Lennox ◽  
Harry Karlinsky
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Elderly Patients ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Late Onset ◽  
Clinical Aspects ◽  
Illustrative Case ◽  
Wide Range

Late-onset Huntington's disease is more common than has been generally appreciated and is associated with a wide range of psychiatric symptoms and syndromes. Geriatric psychiatrists have an important role to play in establishing the diagnosis and providing guidance to elderly patients and their families as they struggle with difficult management decisions. An illustrative case report and selective literature review are presented that highlight the genetic and clinical aspects of the condition.

P158 Increased cell death and striatal redirection leading to impaired olfactory bulb neurogenesis in the adult R6/2 mouse model of Huntington’s disease

Basal Ganglia ◽  
2011 ◽  
Vol 1 (1) ◽  
pp. 38 ◽  
Author(s):  
Z. Kohl ◽  
M. Regensburger ◽  
R. Aigner ◽  
M. Kandasamy ◽  
B. Winner ◽  
...  
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Olfactory Bulb ◽  
Huntington's Disease ◽  
Huntington’S Disease
Sign in / Sign up

Export Citation Format

Share Document