Changes in Cortical and Striatal Neurons Predict Behavioral and Electrophysiological Abnormalities in a Transgenic Murine Model of Huntington's Disease

Laforet, Genevieve; Sapp, Ellen; Chase, Kathryn; McIntyre, Charmian; Boyce, Frederick M.; Campbell, Maura; Cadigan, Beth; Warzecki, L; Tagle, Danilo A.; Reddy, P. Hemachandra; Cepeda, Carlos; Calvert, C. R.; Jokel, Eve S.; Klapstein, Gloria J.; Ariano, Marjorie A.; Levine, Michael S.; DiFiglia, Marian; Aronin, Neil

doi:10.1523/jneurosci.21-23-09112.2001

Cited by 262 publications

(173 citation statements)

References 50 publications

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“…An involvement of HIP1 in the pathogenesis of HD is consistent with the observation that mutant htt impairs neurotransmission in mouse models of HD (Usdin et al, 1999;Li et al, 2000;Laforet et al, 2001;Zeron et al, 2002;Vetter et al, 2003). Mutant htt has been shown to directly interact with the cellular machinery required for synaptic transmission and neuronal function including PACSIN 1/syndapin, syntaxin, endophilin A, and N type channels (Sittler et al, 1998;Modregger et al, 2002;Singaraja et al, 2002;Swayne et al, 2005).…”

supporting

confidence: 82%

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Parker¹,

Metzler²,

Georgiou³

et al. 2007

J. Neurosci.

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Huntingtin-interacting protein 1 (HIP1) was identified through its interaction with htt (huntingtin), the Huntington's disease (HD) protein. HIP1 is an endocytic protein that influences transport and function of AMPA and NMDA receptors in the brain. However, little is known about its contribution to neuronal dysfunction in HD.We report that the Caenorhabditis elegans HIP1 homolog hipr-1 modulates presynaptic activity and the abundance of synaptobrevin, a protein involved in synaptic vesicle fusion. Presynaptic function was also altered in hippocampal brain slices of HIP1 Ϫ/Ϫ mice demonstrating delayed recovery from synaptic depression and a reduction in paired-pulse facilitation, a form of presynaptic plasticity. Interestingly, neuronal dysfunction in transgenic nematodes expressing mutant N-terminal huntingtin was specifically enhanced by hipr-1 loss of function. A similar effect was observed with several other mutant proteins that are expressed at the synapse and involved in endocytosis, such as unc-11/AP180, unc-26/synaptojanin, and unc-57/endophilin.Thus, HIP1 is involved in presynaptic nerve terminal activity and modulation of mutant polyglutamine-induced neuronal dysfunction. Moreover, synaptic proteins involved in endocytosis may protect neurons against amino acid homopolymer expansion.

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supporting

confidence: 82%

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Parker¹,

Metzler²,

Georgiou³

et al. 2007

J. Neurosci.

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“…Synaptic abnormalities have also been reported by others in hippocampal and striatal slice preparations from HD mice (Hodgson et al, 1999;Levine et al, 1999;Usdin et al, 1999;Cepeda et al, 2001Cepeda et al, , 2003Klapstein et al, 2001;Laforet et al, 2001). Some researchers (Hodgson et al, 1999;Usdin et al, 1999) have reported deficits in posttetanic potentiation (PTP) and paired-pulse facilitation, which are indicators of calciumdependent presynaptic mechanisms.…”

Section: Discussionmentioning

confidence: 71%

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

et al. 2005

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Huntington's disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.

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“…Anomalies in the NMDA-evoked current amplitude have been observed in transgenic mice for the mutated full-length Htt, further substantiating the "excitotoxic" hypothesis (7,8). In addition, the striatum in these HD transgenic mice exhibits increased vulnerability to the toxicity of quinolinate (8).…”

mentioning

confidence: 71%

In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration

Bizat¹,

Hermel²,

Humbert

et al. 2003

Journal of Biological Chemistry

123

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The role of caspases and calpains in neurodegeneration remains unclear. In this study, we focused on these proteases in a rat model of Huntington's disease using the mitochondrial toxin 3-nitropropionic acid (3NP). Results showed that 3NP-induced death of striatal neurons was preceded by cytochrome c redistribution, transient caspase-9 processing, and activation of calpain, whereas levels of the active/processed form of caspase-3 remained low and were even reduced as compared with control animals. We evidenced here that this decrease in active caspase-3 levels could be attributed to calpain activation. Several observations supported this conclusion. 1) Pharmacological blockade of calpain in 3NP-treated rats increased the levels of endogenous processed caspase-9 and caspase-3. 2) Cell-free extracts prepared from the striatum of 3NP-treated rats degraded in vitro the p34 and p20 subunits of active recombinant caspase-9 and caspase-3, respectively. 3) This degradation of p34 and p20 could be mimicked by purified -calpain and was prevented by calpain inhibitors. 4) -Calpain produced a loss of the DEVDase (Asp-GluVal-Asp) activity of active caspase-3. 5) Western blot analysis and experiments with 35 S-radiolabeled caspase-3 showed that -calpain cleaved the p20 subunit of active caspase-3 near its catalytic site. 6) -Calpain activity was selectively inhibited (IC 50 of 100 M) by a 12 amino acid peptide corresponding to the C terminus of p20. Our results showed that calpain can down-regulate the caspase-9/caspase-3 cell death pathway during neurodegeneration due to chronic mitochondrial defects in vivo and that this effect may involve, at least in part, direct cleavage of the caspase-3 p20 subunit.

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Changes in Cortical and Striatal Neurons Predict Behavioral and Electrophysiological Abnormalities in a Transgenic Murine Model of Huntington's Disease

Cited by 262 publications

References 50 publications

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and ProtectsCaenorhabditis elegansNeurons against Mutant Polyglutamine Toxicity

Deficits in Experience-Dependent Cortical Plasticity and Sensory-Discrimination Learning in Presymptomatic Huntington's Disease Mice

In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration

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