The selective vulnerability of striatopallidal neurons
Section snippets
Abbreviations
AOAA Amino-oxyacetic acid BDNF Brain derived neurotrophic factor bFGF Basic fibroblast growth factor DHEAS Dehydroepiandrosterone sulphate EAA Excitatory amino acid MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine MSP Medium spiny neuron NADPH Nicotinamide adenine dinucleotide phosphate NGF Nerve growth factor 3NP 3-Nitropropionic acid NO Nitric oxide NOS Nitric oxide synthase NMDA N-Methyl-d-aspartate PCP Phencyclidine SOD Superoxide dismutase
Striatal neurons
There are minor species differences in the anatomical organisation of the striatum and associated structures in rodents and primates (Parent, 1986). The primate striatum contains a structurally distinct caudate nucleus and putamen whereas these structures are not differentiated in the rodent brain and are collectively referred to as the caudateputamen or neostriatum. The striatum of both primates and rodents contains a rostroventral extension which is referred to as the nucleus accumbens
Heritability, symptomatology and basic pathology
Huntington's disease is the best characterised clinical condition which results from striatal degeneration. It is a progressive autosomal dominant disorder. The locus of the defective gene, IT15, has been mapped to the short arm of chromosome 4 Huntington's Disease Collaborative Research Group, 1993, Albin and Tagle, 1995. Huntington's disease belongs to an ever increasing group of diseases characterised by the presence of trinucleotide repeats (Paulson and Fischbeck, 1996). Chromosomes from
Conclusions
Striatal neurons show a range of vulnerabilities to a variety of insults. This can be clearly seen in Huntington's disease where a well mapped pattern of pathological events occurs. MSP neurons are the first striatal cells to be affected as the disease progresses whilst interneurons, in particular the NADPH diaphorase positive ones, are spared even in the late stages of the disease. The MSP neurons, however, are not uniformly affected in Huntington's disease. MSP neurons in the patch
Acknowledgements
Some of the original work presented in this article was supported by the Medical Research Council, The Wellcome Trust and the University of Birmingham.
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Cell-intrinsic glial pathology is conserved across human and murine models of Huntington's disease
2021, Cell ReportsCitation Excerpt :The disease is caused by an expansion of the polyglutamine stretch encoded by the first exon of the gene huntingtin (HTT) (Andrew et al., 1993; Snell et al., 1993). Mutant HTT (mHTT) is ubiquitously expressed in all tissues; however, striatal medium spiny neurons (MSNs) of the basal ganglia and, to a lesser extent, cortical pyramidal neurons display an early and selective vulnerability (Hedreen et al., 1991; Mitchell et al., 1999). Several mechanisms including both toxic gain-of-function and trophic loss-of-function have been implicated in HD pathogenesis, however, the cellular mechanisms underlying the selective vulnerability of MSNs are still unclear (Zuccato et al., 2001; Clabough 2013).
Quality Control in Neurons: Mitophagy and Other Selective Autophagy Mechanisms
2020, Journal of Molecular BiologycAMP-producing chemogenetic and adenosine A2a receptor activation inhibits the inwardly rectifying potassium current in striatal projection neurons
2019, NeuropharmacologyCitation Excerpt :The other group of MSNs (D2-MSNs) heavily express D2Rs and project to GP external part (GPe) and the ventral pallidum, forming the indirect pathway (Gerfen and Bolam, 2017). The profound importance of D2-MSNs is demonstrated when these neurons become dysfunctional: early motor symptoms (abnormal choreic movements) of Huntington's disease is primarily caused by D2-MSN degeneration (Mitchell et al., 1999; Glass et al., 2000; Walker, 2007); experimental ablation or inactivation of D2-MSNs leads to hyperkinesia (Durieux et al., 2009; Bateup et al., 2010; Sano et al., 2013); in mice, D2-MSN overexcitability can also cause cognitive abnormalities or madness (Kellendonk et al., 2006; Snyder, 2006; Simpson and Kellendonk, 2017). Besides the highly expressed D2Rs, another striking feature of D2-MSNs is their intense and selective expression of adenosine A2a receptors (A2aRs) with the expression being far higher than that in any other brain area (Svenningsson et al., 1997, 1998a, b; Svenningsson et al., 1999; Schiffmann et al., 2007; Bogenpohl et al., 2012).