Glutamate Uptake is Reduced in Prefrontal Cortex in Huntington’s Disease

Hassel, Bjørnar; Tessler, Shoshi; Faull, Richard L.M.; Emson, Piers C.

doi:10.1007/s11064-007-9463-1

Cited by 125 publications

(97 citation statements)

References 38 publications

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“…The loss of EAAT2, moreover, parallels the severity of symptoms and cannot be explained by a loss of astrocytes since these cells may actually increase in HD. In addition, when HD postmortem tissue is evaluated for glutamate uptake, a significant decrease is evident even at relatively early stages (50). Similar results have been obtained from HD mice.…”

Section: Rebecsupporting

confidence: 79%

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

Rebec

2013

Antioxidants & Redox Signaling

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Significance: Dysregulation of cortical and striatal neuronal processing plays a critical role in Huntington's disease (HD), a dominantly inherited condition that includes a progressive deterioration of cognitive and motor control. Growing evidence indicates that ascorbate (AA), an antioxidant vitamin, is released into striatal extracellular fluid when glutamate is cleared after its release from cortical afferents. Both AA release and glutamate uptake are impaired in the striatum of transgenic mouse models of HD owing to a downregulation of glutamate transporter 1 (GLT1), the protein primarily found on astrocytes and responsible for removing most extracellular glutamate. Improved understanding of an AA-glutamate interaction could lead to new therapeutic strategies for HD. Recent Advances: Increased expression of GLT1 following treatment with ceftriaxone, a beta-lactam antibiotic, increases striatal glutamate uptake and AA release and also improves the HD behavioral phenotype. In fact, treatment with AA alone restores striatal extracellular AA to wild-type levels in HD mice and not only improves behavior but also improves the firing pattern of neurons in HD striatum. Critical Issues: Although evidence is growing for an AA-glutamate interaction, several key issues require clarification: the site of action of AA on striatal neurons; the precise role of GLT1 in striatal AA release; and the mechanism by which HD interferes with this role. Future Directions: Further assessment of how the HD mutation alters corticostriatal signaling is an important next step. A critical focus is the role of astrocytes, which express GLT1 and may be the primary source of extracellular AA.

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Section: Rebecsupporting

confidence: 79%

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

Rebec

2013

Antioxidants & Redox Signaling

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“…Although previous findings have shown that mutant htt reduces GLT-1 expression in transgenic HD mice (10,22,32) and decreases GLT-1 mRNA and glutamate uptake in the brains of HD patients (33,34), the mechanism underlying this phenomenon has not been revealed.…”

Section: Discussionmentioning

confidence: 90%

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Bradford

Shin

Roberts

et al. 2009

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

328

258

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Huntington disease (HD) is an inherited neurological disorder caused by a polyglutamine expansion in the protein huntingtin and is characterized by selective neurodegeneration that preferentially occurs in striatal medium spiny neurons. Because the medium spiny neurons are innervated abundantly by glutamatergic axons from cortical neurons, the preferential degeneration in the striatal neurons supports the glutamate excitotoxicity theory for HD pathogenesis. Thus, glutamate uptake by glia may be particularly important for preventing glutamate excitotoxicity in HD. Although mutant huntingtin is expressed ubiquitously in various types of cells, it accumulates and forms aggregates in fewer glial cells than in neuronal cells. It remains largely unknown whether and how mutant huntingtin in glia can contribute to the neurological symptoms of HD. We generated transgenic mice that express N-terminal mutant huntingtin in astrocytes, a major type of glial cell that remove extracellular glutamate in the brain. Although transgenic mutant huntingtin in astrocytes is expressed below the endogenous level, it can cause age-dependent neurological phenotypes in transgenic mice. Mice expressing mutant huntingtin show body weight loss, have motor function deficits, and die earlier than wild-type or control transgenic mice. We also found that mutant huntingtin in astrocytes decreases the expression of glutamate transporter by increasing its binding to Sp1 and reducing the association of Sp1 with the promoter of glutamate transporter. These results imply an important role for glial mutant huntingtin in HD pathology and suggest possibilities for treatment.excitotoxicity ͉ glia ͉ neurodegeneration ͉ polyglutamine ͉ glutamate I n Huntington disease (HD), selective neuronal loss occurs preferentially in medium spiny neurons of the striatum and then extends to other brain regions as the disease progresses (1). Because medium spiny neurons are innervated by glutamatergic axons from cortical neurons (2), they are particularly vulnerable to glutamate excitotoxicity, a possible pathogenic mechanism for the preferential neurodegeneration seen in the striatum of HD patients (3). In support of this theory, excitotoxicity of the NMDA receptor, an ionotropic receptor for glutamate, is now associated with HD in various animal models (4, 5).The majority of cells in the brain are glia that support the survival of neuronal cells. Astrocytes are the major type of glia and express glutamate transporters that uptake extracellular glutamate to prevent glutamate neurotoxicity (6-8). Although mutant huntingtin (htt) is expressed in glial cells in the brains of HD mice and patients (9, 10), whether and how mutant htt in glia contributes to neuropathology in vivo remains unknown. Because glial cells can be therapeutic targets, establishing a transgenic mouse model expressing mutant htt specifically in glia can help develop treatment for HD.Current HD mouse models have limitations for studying glial htt contribution, because transgenic htt in these HD mice is e...

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“…Scale bar, 10 m. growth factors. mHtt was found to reduce the transcription of an important neurotransmitter transporter, glutamate transporter (GLT-1; Bradford et al, 2009) in astrocytes, which may contribute to the increased glutamate levels and excitotoxic neuronal death in the brains of HD mice (Espey et al, 1998;Liévens et al, 2001;Behrens et al, 2002;Hassel et al, 2008;Estrada-Sánchez et al, 2009;Bradford et al, 2010;Wolfram-Aduan et al, 2014). Our findings indicate that mHtt can also affect the secretion of neurotrophic factors of astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP

Hong

Zhao

2016

J. Neurosci.

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Brain-derived neurotrophic factor (BDNF) is essential for neuronal differentiation and survival. We know that BDNF levels decline in the brains of patients with Huntington's disease (HD), a neurodegenerative disease caused by the expression of mutant huntingtin protein (mHtt), and furthermore that administration of BDNF in HD mice is protective against HD neuropathology. BDNF is produced in neurons, but astrocytes are also an important source of BDNF in the brain. Nonetheless, whether mHtt affects astrocytic BDNF in the HD brain remains unknown. Here we investigated astrocytes from HD140Q knock-in mice and uncovered evidence that mHtt decreases BDNF secretion from astrocytes, which is mediated by exocytosis in astrocytes. Our results demonstrate that mHtt associates with Rab3a, a small GTPase localized on membranes of dense-core vesicles, and prevents GTP-Rab3a from binding to Rab3-GAP1, disrupting the conversion of GTP-Rab3a into GDP-Rab3a and thus impairing the docking of BDNF vesicles on plasma membranes of astrocytes. Importantly, overexpression of Rab3a rescues impaired BDNF vesicle docking and secretion from HD astrocytes. Moreover, ATP release and the number of ATP-containing dense-core vesicles docking are decreased in HD astrocytes, suggesting that the exocytosis of densecore vesicles is impaired by mHtt in HD astrocytes. Further, Rab3a overexpression reduces reactive astrocytes in the striatum of HD140Q knock-in mice. Our results indicate that compromised exocytosis of BDNF in HD astrocytes contributes to the decreased BDNF levels in HD brains and underscores the importance of improving glial function in the treatment of HD.

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Glutamate Uptake is Reduced in Prefrontal Cortex in Huntington’s Disease

Cited by 125 publications

References 38 publications

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

Dysregulation of Corticostriatal Ascorbate Release and Glutamate Uptake in Transgenic Models of Huntington's Disease

Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms

Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP

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