Presynaptic dysfunction in Huntington's disease

Rozas, José Luis Pastoriza; Gómez‐Sánchez, Leonardo; Tomás-Zapico, Cristina; Lucas, José J.; Fernández‐Chacón, Rafael

doi:10.1042/bst0380488

Cited by 24 publications

(18 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synaptic damage has been extensively reported in neurodegenerative diseases, including Alzheimer’s [111–114,116,117] Parkinson’s [118–122] and Huntington’s [22–23,123–127]. However, the precise factors that cause synaptic degeneration are not completely understood.…”

Section: Synaptic Damage In Huntington’s Diseasementioning

confidence: 99%

Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Reddy

Shirendeb

2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

144

View full text Add to dashboard Cite

Huntington’s disease (HD) is a progressive, fatal neurodegenerative disease caused by an expanded polyglutamine repeats in the HD gene. HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment and emotional disturbances. Research into mutant huntingtin (Htt) and mitochondria has found that mutant Htt interacts with the mitochondrial protein dynamin-related protein 1 (Drp1), enhances GTPase Drp1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. This article summarizes latest developments in HD research and focuses on the role of abnormal mitochondrial dynamics and defective axonal transport in HD neurons. This article also discusses the therapeutic strategies that decrease mitochondrial fragmentation and neuronal damage in HD.

show abstract

Section: Synaptic Damage In Huntington’s Diseasementioning

confidence: 99%

Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Reddy

Shirendeb

2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

144

View full text Add to dashboard Cite

show abstract

“…2009; Lu, 2009; Cepeda et al . 2010; Rozas et al . 2010) have offered opportunities to illuminate the possible links between altered transmitter signalling and neurotoxicity and to assess more subtle modifications in cellular interactions prior to neurodegeneration (see, for example, Milnerwood et al .…”

Section: Introductionmentioning

confidence: 99%

Tonic mGluR5/CB1‐dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin

Dvorzhak

Semtner

Faber

et al. 2013

The Journal of Physiology

View full text Add to dashboard Cite

Key points• In neurodegenerative diseases, the afflicted brain provides both an important object of study and an opportunity to characterize a given cellular interaction from a pathophysiological perspective.• This dual approach is particularly advantageous when human disease is based on a monogenetic defect and an appropriate animal model becomes available for detailed investigation, as in case of Z Q175 KI, a new knock-in mouse expressing a mutant form of murine huntingtin.• Our results challenge the current viewpoint that GABAergic transmission is enhanced in the striatum in Huntington's disease. Quantal analysis in combination with high-frequency stimulation and paired-pulse tests revealed that synaptic GABA release is in fact tonically suppressed, resulting in disinhibition of striatal output activity.• The underlying mechanism involves a retrograde endocannabinoid signalling pathway linking postsynaptic metabotropic glutamate type 5 receptors with presynaptic cannabinoid type 1 receptors and GABA release.• The results help us to understand why pathological elevation of extracellular glutamate levels depresses synaptic inhibition.Abstract Changes in the activity of striatal output neurons (SONs) have been implicated in the pathogenesis of Huntington's disease (HD). In this inherited polyglutamine disorder, accumulation of intracellular toxins causes a variety of deficits, including synaptic dysfunction, but it is still unclear to what extent striatal GABA release is afflicted as well. Two murine HD models were used, a recently created knock-in mouse (Z Q175 KI) and an established model of HD (R6/2). In sagittal slices with relatively well-preserved glutamatergic connections throughout the basal ganglia, we have characterized the following: (i) the excitability of SONs; (ii) their spontaneous action potential-dependent GABAergic synaptic activity; (iii) the capacity of exogenous GABA to inhibit spontaneous action potential generation; and (iv) the properties of GABAergic unitary evoked responses (eIPSCs) in response to intrastriatal minimal stimulation at low and high frequency. The HD SONs exhibited enhanced intrisic excitability and higher levels of GABAergic spontaneous activity without presenting evidence for homeostatic upregulation of endogenous or exogenous GABA actions. Unitary eIPSC amplitudes were reduced, with a clear deficit in the probability of release, as indicated by a higher paired-pulse ratio, failure rate and coefficient of variation. In conditions of high-frequency activation, GABAergic connections of HD SONs were prone to asynchronous release and delayed IPSC generation at the expense of synchronized release. Both in wild-type and in HD SONs, GABA was inhibitory. Our results support the conclusion that the enhanced spontaneous synaptic activity in the HD striatum reflects Abbreviations ACSF, artificial cerebrospinal fluid; AIDA, (RS)-1-aminoindan-1,5-dicarboxylic acid; aIPSCs; asynchronous inhibitory postsynaptic currents; AP, action potential; APV, DL-2-amino-5-phosphonopentanoic acid; ...

show abstract

“…1 D). In contrast, Romero et al (2008) reported elevated resting synaptic Ca 2ϩ levels at the 128Qhtt FL strain with no changes in the frequency of spontaneous release (for review, see Rozas et al, 2010). We nevertheless recorded a higher MEPP frequency in R6/1 junctions after high-frequency stimulation trains, but we cannot distinguish whether such an increase is due to (1) abnormally high cytosolic [Ca 2ϩ ], (2) an effect downstream of a Ca 2ϩ -dependent step of exocytosis activation, or (3) both.…”

Section: Alterations In Camentioning

confidence: 99%

“…Although htt is ubiquitously expressed in neuronal and non-neuronal cells, the most vulnerable neurons in HD are the striatal medium spiny neurons and the cortical pyramidal neurons. Likely, mutant-htt becomes toxic through multiple molecular mechanisms, including synaptic dysfunction (Smith et al, 2005;Rozas et al, 2010). Detailed studies of synaptic alterations in HD mouse models in the brain regions that typically degenerated in HD have reported different phenotypes depending on synaptic type, brain region, and level of degeneration (Zeron et al, 2002;Cepeda et al, 2003Cepeda et al, , 2007Smith et al, 2005;Cummings et al, 2009;Rozas et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Increased Neurotransmitter Release at the Neuromuscular Junction in a Mouse Model of Polyglutamine Disease

Rozas¹,

Gómez‐Sánchez²,

Tomás-Zapico³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice). We have found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-␣, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats.

show abstract

Presynaptic dysfunction in Huntington's disease

Cited by 24 publications

References 51 publications

Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease

Tonic mGluR5/CB1‐dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin

Increased Neurotransmitter Release at the Neuromuscular Junction in a Mouse Model of Polyglutamine Disease

Contact Info

Product

Resources

About