Modeling Brain Reserve: Experience-Dependent Neuronal Plasticity in Healthy and Huntington's Disease Transgenic Mice

Nithianantharajah, Jess; Barkus, Christopher; Vijiaratnam, Nirosen; Olivier, C; Hannan, Anthony J.

doi:10.1097/jgp.0b013e318196a632

Cited by 44 publications

(22 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, WT animals raised in environmentally enriched conditions show subtle alterations in dendritic complexity; however, spine density was unchanged. Similarly, Nithianantharajah et al, (2009), utilizing a similar enrichment paradigm to the one in this study, also showed no effect of enrichment rearing on spine number in the CA1 region. Many of the reported effects on structural plasticity following enrichment are from studies utilizing rats, a considerably different model from mice.…”

Section: Discussionmentioning

confidence: 78%

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Burrows

McOmish

Buret

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

Schizophrenia arises from a complex interplay between genetic and environmental factors. Abnormalities in glutamatergic signaling have been proposed to underlie the emergence of symptoms, in light of various lines of evidence, including the psychotomimetic effects of NMDA receptor antagonists. Metabotropic glutamate receptor 5 (mGlu5) has also been implicated in the disorder, and has been shown to physically interact with NMDA receptors. To clarify the role of mGlu5-dependent behavioral expression by environmental factors, we assessed mGlu5 knockout (KO) mice after exposure to environmental enrichment (EE) or reared under standard conditions. The mGlu5 KO mice showed reduced prepulse inhibition (PPI), long-term memory deficits, and spontaneous locomotor hyperactivity, which were all attenuated by EE. Examining the cellular impact of genetic and environmental manipulation, we show that EE significantly increased pyramidal cell dendritic branching and BDNF protein levels in the hippocampus of wild-type mice; however, mGlu5 KO mice were resistant to these alterations, suggesting that mGlu5 is critical to these responses. A selective effect of EE on the behavioral response to the NMDA receptor antagonist MK-801 in mGlu5 KO mice was seen. MK-801-induced hyperlocomotion was further potentiated in enriched mGlu5 KO mice and treatment with MK-801 reinstated PPI disruption in EE mGlu5 KO mice only, a response that is absent under standard housing conditions. Together, these results demonstrate an important role for mGlu5 in environmental modulation of schizophreniarelated behavioral impairments. Furthermore, this role of the mGlu5 receptor is mediated by interaction with NMDA receptor function, which may inform development of novel therapeutics.

show abstract

Section: Discussionmentioning

confidence: 78%

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Burrows

McOmish

Buret

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Degenerative changes in MSN morphology have been found in multiple HD models [48], [49], [50], [51], however, striatal MSN morphology has only been reported for YAC128 mice at one month of age with no alterations identified [38], [52]. Neuron morphology studies of striatal MSNs in R6/1[48], R6/2 [50], HD48 and HD89 [49] mice showed decreases in spine density across branch order that were only evident in symptomatic mice [50].…”

Section: Discussionmentioning

confidence: 95%

Disease-Toxicant Interactions in Manganese Exposed Huntington Disease Mice: Early Changes in Striatal Neuron Morphology and Dopamine Metabolism

et al. 2012

View full text Add to dashboard Cite

YAC128 Huntington's disease (HD) transgenic mice accumulate less manganese (Mn) in the striatum relative to wild-type (WT) littermates. We hypothesized that Mn and mutant Huntingtin (HTT) would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl2-4H2O (50 mg/kg) on days 0, 3 and 6. Striatal medium spiny neuron (MSN) morphology, as well as levels of dopamine (DA) and its metabolites (which are known to be sensitive to Mn-exposure), were analyzed at 13 weeks (7 days from initial exposure) and 16 weeks (28 days from initial exposure). No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology.

show abstract

“…Interventions to ameliorate and, ultimately, prevent the development of the HD phenotype should therefore occur early to target neuronal dysfunction in both the cortex and striatum 29. Some of the preserved functional capability in the face of severe striatal pathology found in our study could also suggest a degree of cognitive reserve30 or variability in regional HD gene expression within specific brain areas 31. The advent of better functional and structural imaging in these neurodegenerative conditions holds promise for integrating clinical information on functional and cognitive status with the progress of neurodegenerative pathology.…”

Section: Discussionmentioning

confidence: 78%

Clinical severity of Huntington's disease does not always correlate with neuropathologic stage

et al. 2012

View full text Add to dashboard Cite

Background Huntington’s disease is an inherited neurodegenerative disorder caused by a triplet repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in Huntington’s disease. Methods The brains of 24 patients with a clinical and genetic diagnosis of Huntington’s disease were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (Stage 1–2, n=7) or severe (Stage 3–4, n=17). Clinical severity was assessed on the basis of the Mini Mental State Exam (0–30) and two Unified Huntington's Disease Rating Scale functional components, the Independence Scale (10–100) and the Total Functional Capacity (0–13). Results The mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death, and less well educated. Despite obvious clinical and pathological differences between mild-moderate and severe Huntington’s disease subjects at autopsy, mean Mini Mental State Exam scores of the two groups prior to death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores prior to death were low and not statistically significant. Conclusions Our results suggest that the extent of striatal changes in Huntington’s disease may not always correlate with clinical disease severity measured by Unified Huntington's Disease Rating Scale functional scales.

show abstract

Modeling Brain Reserve: Experience-Dependent Neuronal Plasticity in Healthy and Huntington's Disease Transgenic Mice

Cited by 44 publications

References 59 publications

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Environmental Enrichment Ameliorates Behavioral Impairments Modeling Schizophrenia in Mice Lacking Metabotropic Glutamate Receptor 5

Disease-Toxicant Interactions in Manganese Exposed Huntington Disease Mice: Early Changes in Striatal Neuron Morphology and Dopamine Metabolism

Clinical severity of Huntington's disease does not always correlate with neuropathologic stage

Contact Info

Product

Resources

About