Neurobiology of disease
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Neurobiology of disease · Aug 2011
Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity.
Pharmacological blockade of NR2B-containing N-methyl-d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation are crucially influenced by their synaptic vs extrasynaptic localization, and both NMDAR function and localization are dependent on the presence of the NR2B subunit and its phosphorylation state. We investigated whether changes in NR2B subunit phosphorylation, and alterations in its neuronal membrane localization and cellular expression occur during epileptogenesis, and if these changes are involved in neuronal cell loss. ⋯ The NR2B phosphorylation changes detected at completion of status epilepticus, and interictally in the chronic phase of spontaneous seizures, are predictive of receptor translocation from synaptic to extrasynaptic sites. Pharmacological blockade of NR2B-containing NMDARs by ifenprodil administration during epileptogenesis significantly reduced pyramidal cell loss in the hippocampus, showing that the observed post-translational and cellular changes of NR2B subunit contribute to excitotoxicity. Therefore, pharmacological targeting of misplaced NR2B-containing NMDARs, or prevention of these NMDAR changes, should be considered to block excitotoxicity which develops after various pro-epileptogenic brain injuries.
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Neurobiology of disease · Jun 2011
Connectivity-based segmentation of the striatum in Huntington's disease: vulnerability of motor pathways.
The striatum, the primary site of degeneration in Huntington's disease (HD), connects to the cerebral cortex via topographically organized circuits subserving unique motor, associative and limbic functions. Currently, it is not known whether all cortico-striatal circuits are equally affected in HD. We aimed to study the selective vulnerability of individual cortico-striatal circuits within the striatum in HD, and hypothesized that motor cortico-striatal pathways would be most affected, consistent with HD being a primarily motor disorder. ⋯ In HD patients, the greatest difference from controls in volume, FA and MD was observed in M1 and S1 subregions of the caudate and putamen. Motor symptoms correlated with volume and MD in sensorimotor striatal subregions, suggesting that sensorimotor striatal degeneration is closely related to motor dysfunction. DTI tractography provides a novel approach to sensitively examine circuit-specific abnormalities in HD and has identified that the motor cortico-striatal circuit is selectively vulnerable in HD.
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Neurobiology of disease · Jun 2011
Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease.
6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2 μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2 μl per site, termed "striatum(2 × 1 μl)" and "striatum(2 × 2 μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1 μl per site). ⋯ In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2 × 2 μl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum.
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Neurobiology of disease · Jun 2011
"Brain training" improves cognitive performance and survival in a transgenic mouse model of Huntington's disease.
Environmental enrichment (EE) has been shown to improve neurological function and cognitive performance in animal models of Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). We have shown recently that even when they are already living in an enriched environment, additional EE had beneficial effects in R6/2 mice. Here we examined the effects of three different enrichment paradigms on cognitive dysfunction in R6/2 mice in a longitudinal study. ⋯ These effects became apparent after as little as 2 weeks of training in the OX maze. These data suggest that there is a cognitive reserve that may be exploited in neurodegenerative disease. While brain training was not beneficial for all mice, it produced no deleterious effects, and so warrants further study in rodent models of HD.
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Neurobiology of disease · May 2011
ReviewHereditary dystonia as a neurodevelopmental circuit disorder: Evidence from neuroimaging.
Primary dystonia has traditionally been viewed as a basal ganglia disorder, but recent studies suggest that the cerebellum plays a crucial role in the disease. Primary dystonia is associated with several genotypes. Among those, DYT1 and DYT6 are inherited in autosomal dominant fashion with reduced penetrance. ⋯ The microstructural deficits in cerebellar outflow are linked to an abnormally elevated sensorimotor network (NMRP) in dystonia patients. Abnormal expression of this network is reduced by successful treatment with deep brain stimulation. This article is part of a Special Issue entitled "Advances in dystonia".