Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Bauer, Andreas; Zilles, Karl; Matusch, Andreas; Holzmann, Carsten; Rieß, Olaf; Hoersten, Stephan von

doi:10.1111/j.1471-4159.2005.03351.x

Cited by 5 publications

(8 citation statements)

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“…In the striatum of transgenic mouse or rat models of HD, no changes in benzodiazepine or GABA binding 63,64 or a slight, albeit significant increase 65 have been reported. Functional and molecular analyses of GABAergic neurotransmission in the striatum have revealed complex changes in this brain structure ( Figure 2).…”

Section: Alter Ati On Of G Aba Neurotr Ans Miss Ion In Ms Nsmentioning

confidence: 95%

“…Interestingly, quantitative autoradiography has been used to assess neurotransmitter receptor densities in several brain regions in a rat model for the HD mutation. 63 These analyses showed that the expression levels of receptors of the cholinergic, dopaminergic, serotoninergic, noradrenergic, glutamatergic, and GABAergic systems are either increased, decreased, or remain unchanged. These findings in turn suggest that receptor alterations in HD are subtype selective and regionally differential.…”

Section: Alter Ati On Of the G Aba Sys Tem In The Hd B R Ainmentioning

confidence: 99%

“…Based on analyses with point-mutated mice of a benzodiazepine binding site, it was possible to attribute specific behavioral responses following benzodiazepine treatments to specific GABA A Rs comprising either α1, α2, α3, or α5 subunits, thereby providing the opportunity to selectively modulate brain areas or neuronal networks (review in 128 ). In HD, changes in GABA A R subtype expression are specific not only to brain area 53,63,69,101,129 but also to neuronal cell type. 66,69 The fact that the expression of GABA A R subunits in the different striatal neuron classes is differentially altered suggests that subtype-specific benzodiazepine drugs may act on particular symptoms linked to HD disorders.…”

Section: P Otential Ther Apeuti C Aven Ue Smentioning

confidence: 99%

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Alteration of GABAergic neurotransmission in Huntington's disease

Garret

Chazalon

et al. 2018

CNS Neurosci Ther

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Hereditary Huntington's disease (HD) is characterized by cell dysfunction and death in the brain, leading to progressive cognitive, psychiatric, and motor impairments. Despite molecular and cellular descriptions of the effects of the HD mutation, no effective pharmacological treatment is yet available. In addition to well-established alterations of glutamatergic and dopaminergic neurotransmitter systems, it is becoming clear that the GABAergic systems are also impaired in HD. GABA is the major inhibitory neurotransmitter in the brain, and GABAergic neurotransmission has been postulated to be modified in many neurological and psychiatric diseases. In addition, GABAergic neurotransmission is the target of many drugs that are in wide clinical use. Here, we summarize data demonstrating the occurrence of alterations of GABAergic markers in the brain of HD carriers as well as in rodent models of the disease. In particular, we pinpoint HD-related changes in the expression of GABA receptors (GABA Rs). On the basis that a novel GABA pharmacology of GABA Rs established with more selective drugs is emerging, we argue that clinical treatments acting specifically on GABAergic neurotransmission may be an appropriate strategy for improving symptoms linked to the HD mutation.

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Section: Alter Ati On Of G Aba Neurotr Ans Miss Ion In Ms Nsmentioning

confidence: 95%

Section: Alter Ati On Of the G Aba Sys Tem In The Hd B R Ainmentioning

confidence: 99%

Section: P Otential Ther Apeuti C Aven Ue Smentioning

confidence: 99%

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Alteration of GABAergic neurotransmission in Huntington's disease

Garret

Chazalon

et al. 2018

CNS Neurosci Ther

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“…Reduced levels of serotonin have been found in animal and human HD studies. [9][10][11][12][13][14][15] Treatment trials with selective serotonin reuptake inhibitors (SSRIs) have shown improved symptoms in HD mice, 13,16 yet only 1 randomized controlled trial (RCT) using an SSRI (fluoxetine) in adults with HD has been conducted. 17 The current trial is the first RCT in HD with the primary endpoint of improved executive function.…”

mentioning

confidence: 99%

Results of the citalopram to enhance cognition in Huntington disease trial

et al. 2013

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Objective Evaluate citalopram for executive functioning in HD. Design Randomized, double-blind, placebo-controlled. Patients Thirty-three adults with HD, cognitive complaints and no depression (Hamilton Depression Rating Scale ≤12). Intervention Citalopram 20 mg or placebo [7 visits, 20 weeks], with practice and placebo run-ins. Primary Outcome Change in executive functioning. Results Intent to treat analysis controlling for practice effects comparing visits 1–2 to 5–6 for citalopram vs. placebo. There were no significant benefits on the executive function composite (treatment-placebo mean difference −0.167 95% CI (−0.361 to 0.028), p=.092). Citalopram participants showed improved clinician-rated depression symptoms on the HAM-D (t=−2.02, p=0.05). There were no group differences on motor ratings, self-reported executive functions, psychiatric symptoms or functional status. Conclusion No evidence that short-term treatment with citalopram improved executive functions in HD. Despite excluding patients with active depression, participants on citalopram showed improved mood, raising the possibility of efficacy for subsyndromal depression in HD.

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“…The possibilities include an upregulation of the NMDA receptors in older brains, an increase in Ca 2+ levels due to the release from ER and ⁄ or to mitochondrial dysfunctions. Because some evidence from the literature did not support the hypothesis of the increase in NMDA receptors in HD (Young et al, 1988;von Horsten et al, 2003;Bauer et al, 2005) or in R6 ⁄ 1 and R6 ⁄ 2 mice models (Cha et al, 1998(Cha et al, , 1999NicNiocaill et al, 2001), we investigated the effect of Glu in the absence of external Ca 2+ . In fact, Glu response in these conditions was not significantly different than the response in the presence of external Ca 2+ , indicating that participation of NMDA receptors in this response is more important in transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Glutamate‐induced alterations in Ca²⁺ signaling are modulated by mitochondrial Ca²⁺ handling capacity in brain slices of R6/1 transgenic mice

Rosenstock

Bertoncini

Teles

et al. 2010

Eur J of Neuroscience

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Huntington's disease is a neurodegenerative disorder caused by an expansion of CAGs repeats and characterized by alterations in mitochondrial functions. Although changes in Ca(2+) handling have been suggested, the mechanisms involved are not completely understood. The aim of this study was to investigate the possible alterations in Ca(2+) handling capacity and the relationship with mitochondrial dysfunction evaluated by NAD(P)H fluorescence, reactive oxygen species levels, mitochondrial membrane potential (DeltaPsi(m)) measurements and respiration in whole brain slices from R6/1 mice of different ages, evaluated in situ by real-time real-space microscopy. We show that the cortex and striatum of the 9-month-old R6/1 transgenic mice present a significant sustained increase in cytosolic Ca(2+) induced by glutamate (Glu). This difference in Glu response was partially reduced in R6/1 when in the absence of extracellular Ca(2+), indicating that N-methyl-D-aspartate receptors participation in this response is more important in transgenic mice. In addition, Glu also lead to a decrease in NAD(P)H fluorescence, a loss in DeltaPsi(m) and a further increase in respiration, which may have evoked a decrease in mitochondrial Ca(2+) Ca(2+)(m) uptake capacity. Taken together, these results show that alterations in Ca(2+) homeostasis in transgenic mice are associated with a decrease in Ca(2+)(m) uptake mechanism with a diminished Ca(2+) handling ability that ultimately causes dysfunctions and worsening of the neurodegenerative and the disease processes.

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Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Abstract: Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation.

Cited by 5 publications

References 1 publication

Alteration of GABAergic neurotransmission in Huntington's disease

Alteration of GABAergic neurotransmission in Huntington's disease

Results of the citalopram to enhance cognition in Huntington disease trial

Glutamate‐induced alterations in Ca²⁺ signaling are modulated by mitochondrial Ca²⁺ handling capacity in brain slices of R6/1 transgenic mice

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Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation

Abstract: Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation.

Cited by 5 publications

References 1 publication

Alteration of GABAergic neurotransmission in Huntington's disease

Alteration of GABAergic neurotransmission in Huntington's disease

Results of the citalopram to enhance cognition in Huntington disease trial

Glutamate‐induced alterations in Ca2+ signaling are modulated by mitochondrial Ca2+ handling capacity in brain slices of R6/1 transgenic mice

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Glutamate‐induced alterations in Ca²⁺ signaling are modulated by mitochondrial Ca²⁺ handling capacity in brain slices of R6/1 transgenic mice