Differential Susceptibility to Excitotoxic Stress in YAC128 Mouse Models of Huntington Disease between Initiation and Progression of Disease

Graham, Rona K.; Pouladi, Mahmoud A.; Joshi, Prasad; Lu, Ge; Deng, Yu; Wu, Nanping; Figueroa, Bryan E.; Metzler, Martina; André, Véronique; Slow, Elizabeth; Raymond, Lynn A.; Friedlander, Robert M.; Levine, Michael S.; Leavitt, Blair R.; Hayden, Michael R.

doi:10.1523/jneurosci.5473-08.2009

Cited by 116 publications

(156 citation statements)

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“…Finally, we also found that chronic treatment with the highly selective M 4 PAM VU0467154 prevents or delays the onset of deficits in both striatal glutamatergic and dopaminergic signaling that are observed in 5-mo-old YAC128 mice and also improves motor symptoms detected at this age. An early increase in corticostriatal glutamatergic transmission has been described previously in multiple mouse models of HD (8,(11)(12)(13)(14). These changes could contribute to early vulnerability of SPNs to excitotoxicity and synaptic alterations (11).…”

Section: Discussionmentioning

confidence: 54%

“…An early increase in corticostriatal glutamatergic transmission has been described previously in multiple mouse models of HD (8,(11)(12)(13)(14). These changes could contribute to early vulnerability of SPNs to excitotoxicity and synaptic alterations (11).…”

Section: Discussionmentioning

confidence: 54%

“…Importantly, the late "hypoglutamatergic" state has been described in previous studies, showing that symptomatic stages are characterized by loss of corticostriatal presynaptic and postsynaptic glutamatergic function and also by alteration in synaptic plasticity (8,11,14,(48)(49)(50). This corticostriatal "disconnection" (8) could be responsible, at least in part, for motor and cognitive dysfunction seen at later ages.…”

Section: Discussionmentioning

confidence: 74%

“…Due to its pivotal importance in these domains, changes in striatal physiology can contribute to multiple neurological diseases, including Huntington's disease, Parkinson's disease, dystonia, and others. An increasing number of reports suggest that changes in striatal synaptic physiology, including changes at glutamatergic, dopaminergic, and cholinergic synapses, are evident beginning in the prediagnostic phase of HD (5,6,(8)(9)(10)(11)(12)(13)(14)(35)(36)(37). These changes may contribute to early motor, cognitive, and psychiatric abnormalities, and could set the stage for the extensive pathophysiological alterations appearing later in the striatum.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Activation of caspase‐6 and cleavage of caspase‐6 substrates is an early event in NMDA receptor–mediated excitotoxicity

Girling

Demers

Lainé

et al. 2017

J of Neuroscience Research

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Excitotoxicity, due to overstimulation of N-methyl D-aspartate receptors (NMDARs), has a pivotal role in many neurological disorders. However, NMDAR antagonists often cause side effects, and identifying more druggable therapeutic targets for NMDAR excitotoxicity is an important goal. Activation of caspases is a downstream effect of excitotoxicity that may be critically involved in NMDAR-mediated cell death. Caspase-6 (casp6) in particular has been shown to play a key role in the pathogenesis of stroke, Huntington disease, and Alzheimer disease. Using N-methyl D-aspartate (NMDA)-induced excitotoxic injuries of primary rat neurons, we demonstrate that there is an early increase in caspase profiles after an excitotoxic event at the level of mRNA, protein, and activity. Casp6 is elevated and activated first, followed by caspase-8 and caspase-3. Similarly, known casp6 substrates huntingtin, as well as novel casp6 substrates serine/threonine kinase 3 and death domain-associated protein, are cleaved in similar temporal patterns post NMDA. On the basis of these data, we propose that casp6 may be an initiator caspase in apoptotic cascades leading to neuronal death after an excitotoxic event and suggest casp6 as a potential therapeutic target for neurological disorders where NMDAR-mediated excitotoxicity has been shown to play a role.

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Neurochemical correlates of caudate atrophy in Huntington's disease

et al. 2014

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BACKGROUND The precise pathogenic mechanisms of Huntington disease (HD) are unknown, but can be tested in vivo using proton magnetic resonance spectroscopy (1H MRS) to measure neurochemical changes. OBJECTIVE To evaluate neurochemical differences in HD gene mutation-carriers (HGMC) vs. controls, and to investigate relationships among function, brain structure and neurochemistry in HD. Since previous 1H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two 1H MRS data analysis approaches. METHODS HGMC with pre-manifest to early HD and controls underwent evaluation of motor function, MR imaging and localized 1H MRS in caudate and frontal lobe. Analytical approaches tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). RESULTS We identified a suite of neurochemicals reduced in concentration proportionally to loss of caudate volume in HGMC. Caudate concentrations of NAA, creatine, choline, and caudate and frontal concentrations of glutamate+glutamine and glutamate correlated with caudate volume in HGMC subjects. The relative, but not the absolute quantitation approach revealed disease-related differences; the Glx signal was decreased relative to other neurochemicals in caudate of HGMC subjects vs. controls. CONCLUSIONS This is the first study to demonstrate correlation among structure, function and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable magnification of subtle differences between groups. Observation of decreased glutamate-glutamine signals suggests that glutamate signaling may be disrupted relatively early in HD, with important implications for therapeutic approaches.

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Differential Susceptibility to Excitotoxic Stress in YAC128 Mouse Models of Huntington Disease between Initiation and Progression of Disease

Cited by 116 publications

References 86 publications

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

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

Activation of caspase‐6 and cleavage of caspase‐6 substrates is an early event in NMDA receptor–mediated excitotoxicity

Neurochemical correlates of caudate atrophy in Huntington's disease

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Differential Susceptibility to Excitotoxic Stress in YAC128 Mouse Models of Huntington Disease between Initiation and Progression of Disease

Cited by 116 publications

References 86 publications

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

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

Activation of caspase‐6 and cleavage of caspase‐6 substrates is an early event in NMDA receptor–mediated excitotoxicity

Neurochemical correlates of caudate atrophy in Huntington's disease

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

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