Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice

Milnerwood, Austen J.; Gladding, Clare M.; Pouladi, Mahmoud A.; Kaufman, Alexandra M.; Hines, Rochelle M.; Boyd, Jeffrey E.; Ko, Rebecca W.Y.; Vasuta, Oana Cristina; Graham, Rona K.; Hayden, Michael R.; Murphy, Timothy H.; Raymond, Lynn A.

doi:10.1016/j.neuron.2010.01.031

Cited by 135 publications

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“…A low dose of memantine rescues neuropathological and behavioural phenotypes as well as electrophysiological abnormalities in models of HD. By contrast, high dose memantine worsens these symptoms 24,29 . Similarly, administration of a low memantine dose corrected defects in learning and memory tasks, such as performance in the Morris water maze and passive avoidance learning in a mouse model of AD 30 .…”

Section: Therapeutic Approachesmentioning

confidence: 98%

“…The presence of Aβ oligomers, early intermediates in the Aβ aggregation pathway, has in turn been associated with increased activation of extrasynaptic NMDARs, which could cause a feedback loop leading to synaptic dysfunction 28 . However, the strongest evidence for the role of extrasynaptic NMDAR in cognitive impairment is the effectiveness of memantine, an NMDAR blocker (see below), in rodent models of HD and AD as well as in AD patients 24,[29][30][31] .…”

Section: Aberrant Extrasynaptic Nmda Receptor Activity In Hd and Admentioning

confidence: 99%

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Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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Section: Therapeutic Approachesmentioning

confidence: 98%

Section: Aberrant Extrasynaptic Nmda Receptor Activity In Hd and Admentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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“…It is worth noting that NMDAR-dependent plasticity and transmission are altered in Huntington ' s disease transgenic mice much before the onset of motor defi cits. Two important recent papers provided strong arguments suggesting that the balance between synaptic and extrasynaptic NMDAR activity could be crucial in determining neuronal cell survival in Huntington ' s disease (Okamoto et al , 2009 ;Milnerwood et al , 2010 ). These studies were performed on YAC128 transgenic mice expressing mutant full-length human huntingtin (mtHTT) protein that contains a 128-length polyglutamine expansion.…”

Section: Nmdar Activation and Neuronal A β Synthesismentioning

confidence: 99%

“…The effi cacy of memantine to antagonize neurodegenerative pathways has been elegantly demonstrated in the context of Hungtinton ' s disease pathology in recent in vivo studies (Okamoto et al , 2009 ;Milnerwood et al , 2010 ). Given the link evidenced between NMDAR dysregulation and AD (see above), it seemed pertinent to evaluate the capacity of memantine to modulate A β release in in vitro and/or in vivo models.…”

Section: Targeting Extrasynaptic Nmdars To Lower a β Peptide: Interesmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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“…At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3)(4)(5)(6)(7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

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confidence: 99%

Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

Pancani

Foster

Moehle

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutations that lead to Huntington's disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M 4 subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M 4 positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M 4 PAMs could provide a therapeutic strategy for the treatment of HD.neurodegenerative | basal ganglia | movement disorder | trinucleotide repeat disorder H untington's disease (HD) is a rare and fatal neurodegenerative disease caused by an expansion of a CAG triplet repeat in Htt, the gene that encodes for the protein huntingtin (1, 2). HD is characterized by a prediagnostic phase that includes subtle changes in personality, cognition, and motor function, followed by a more severe symptomatic stage initially characterized by hyperkinesia (chorea), motor incoordination, deterioration of cognitive abilities, and psychiatric symptoms. At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3-7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6-16).Striatal spiny projection neurons (SPNs) receive large glutamatergic inputs from the cortex and thalamus, as well as dopaminergic innervation from the substantia nigra. In the healthy striatum, the interplay of these neurotransmitters coordinates the activity of SPNs and striatal interneurons, regulating motor planning and execution as well as cognition and motivation (17, 18). Htt mutations lead to an early increase in striatal glutamatergic transmission, which begins during the asymptomatic phase of HD (12-14) and could contribute to synaptic changes observed in later stages of HD (19,20). Based on this, pharmacological agents that reduce excitatory transmission in the striatum could reduce or prevent the progression of alterations in striatal synaptic function and behavior observed in symptomatic stages of HD.Muscarinic acetylcholine receptors (mAChRs), particularly M 4 , can inhibit transmission at corticostriatal synapses (21-25). Therefore, it is possible that selective activation of specific mAChR subtypes could normalize excessive corticostriatal t...

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Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice

Abstract: The following is the corrected Acknowledgments section, which includes funding information that was missing from the previous version.

Cited by 135 publications

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Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

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Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice

Abstract: The following is the corrected Acknowledgments section, which includes funding information that was missing from the previous version.

Cited by 135 publications

References 0 publications

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

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Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice