A primate model of Huntington's disease: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon

Hantraye, Philippe; Riché, D.; Mazière, M.; Isacson, Ole

doi:10.1016/0014-4886(90)90014-j

Cited by 167 publications

(68 citation statements)

References 46 publications

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“…Studies in primate models have shown that dystonia is associated with a reduction of activity along the putamen-GPe connection, and increased inhibition of STN and GPi by GPe efferents [193,194]. Based on pharmacologic studies, there seems to be a relative increase in the activity of striatal neurons of the direct pathway over those that give rise to the indirect pathway in dystonia [195,196], and single-cell recording studies in patients undergoing functional neurosurgical treatments have demonstrated low discharge rates in both GPe and GPi [197][198][199][200][201][202], in distinction to the aforementioned changes in PD where GPi discharge rates are generally increased.…”

Section: Dystoniamentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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Deep brain stimulation (DBS) is highly effective for both hypo-and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal gangliathalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

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Section: Dystoniamentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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“…Initially, this hypothesis was based on studies of postmortem human brain showing a disproportionate loss of striatal NMDARs in early-stage HD (Young et al, 1988;Albin et al, 1990) and striatal injection of NMDAR agonists in rodents or nonhuman primates that reproduced the pattern of neuronal damage seen in HD (Beal et al, 1986(Beal et al, , 1991Sanberg et al, 1989;Hantraye et al, 1990;Ferrante et al, 1993). Recent findings in transgenic mouse models also support this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Altered NMDA Receptor Trafficking in a Yeast Artificial Chromosome Transgenic Mouse Model of Huntington's Disease

Fan¹,

Fernandes²,

Zhang³

et al. 2007

J. Neurosci.

110

111

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Overactivation of NMDA receptors (NMDARs) is believed to play a role in degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). This hereditary disorder is caused by an expansion Ͼ35 in the polyglutamine (polyQ) region of the protein huntingtin (htt). Previous work has shown that NMDAR current, calcium signaling, and/or toxicity are enhanced in striatal MSNs in a variety of transgenic mice and cellular models of HD, but whether the enhancement is specific for MSNs or correlated with mutant htt (mhtt) polyQ length is not known. Furthermore, the mechanism underlying the increase in NMDAR activity has not been elucidated. Here we report polyQ length-dependent enhancement of peak NMDAR current density by mhtt in cultured MSNs, but not cortical neurons, from the yeast artificial chromosome (YAC) transgenic HD mouse model. We also observed a shift of NMDAR subunits NR1 and NR2B from internal pools to the plasma membrane and a significantly faster rate of NMDAR insertion to the surface in YAC72 MSNs. In comparing YAC72 with wild-type striatal tissue, subcellular fractionation revealed a relative enrichment of NR1 C2Ј-containing NMDARs in the vesicle/microsome-enriched fraction, and coimmunoprecipitation experiments demonstrated an increased proportion of NR1 C2Ј isoforms associated with NR2 subunits, which may contribute to faster forward trafficking of these receptors. Our results suggest that altered NMDAR trafficking may underlie potentiation of NMDAR-mediated current and toxicity in the YAC72 HD mouse model. This polyQ length-dependent, neuronal-specific change in NMDAR activity induced by mhtt may contribute to selective neuronal degeneration in HD.

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“…Glutamate mediates most fast excitatory synaptic transmission in the brain through activation of three subclasses of ionotropic receptors: NMDA, kainate, and a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) (Monaghan et al, 1989). In animals, overactivation of the NMDA receptor subclass in neostriatum most closely reproduces the neuropathological, neurochemical, and behavioral changes of HD (Dawbarn et al, 1985;Ferrante et al, 1985;Beal et al, 1986Beal et al, , 1989Sanberg et al, 1989;Hantraye et al, 1990). As well, postmortem analysis of brain tissue from patients with HD suggests that neurons with high expression of NMDA receptors are particularly vulnerable to degeneration (Young et al, 1988;Albin et al, 1990).…”

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confidence: 99%

Subtype‐Specific Enhancement of NMDA Receptor Currents by Mutant Huntingtin

Chen¹,

Luo²,

Wellington³

et al. 1999

Journal of Neurochemistry

177

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Evidence suggests that NMDA receptor-mediated neurotoxicity plays a role in the selective neurodegeneration underlying Huntington's disease (HD). The gene mutation that causes HD encodes an expanded polyglutamine tract of >35 in huntingtin, a protein of unknown function. Both huntingtin and NMDA receptors interact with cytoskeletal proteins, and, for NMDA receptors, such interactions regulate surface expression and channel activity. To determine whether mutant huntingtin alters NMDA receptor expression or function, we coexpressed mutant or normal huntingtin, containing 138 or 15 glutamine repeats, respectively, with NMDA receptors in a cell line and then assessed receptor channel function by patch-clamp recording and surface expression by western blot analysis. It is interesting that receptors composed of NR1 and NR2B subunits exhibited significantly larger currents when coexpressed with mutant compared with normal huntingtin. Moreover, this effect was selective for NRl/NR2B, as NRl/NR2A showed similar currents when coexpressed with mutant versus normal huntingtin. However, ion channel properties and total surface expression of the NR1 subunit were unchanged in cells cotransfected with NRl/NR2B and mutant huntingtin. Our results suggest that mutant huntingtin may increase numbers of functional NRl/NRPB-type receptors at the cell surface. Because NRl/NR2B is the predominant NMDA receptor subtype expressed in medium spiny neostriatal neurons, our findings may help explain the selective vulnerability of these neurons in HD.

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A primate model of Huntington's disease: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon

Cited by 167 publications

References 46 publications

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

Altered NMDA Receptor Trafficking in a Yeast Artificial Chromosome Transgenic Mouse Model of Huntington's Disease

Subtype‐Specific Enhancement of NMDA Receptor Currents by Mutant Huntingtin

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