Elsevier

Progress in Neurobiology

Volume 59, Issue 6, December 1999, Pages 691-719
Progress in Neurobiology

The selective vulnerability of striatopallidal neurons

https://doi.org/10.1016/S0301-0082(99)00019-2Get rights and content

Abstract

The different types of striatal neuron 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.

Medium spiny projection (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 themselves are also differentially affected. The death of MSP neurons in the patch compartment of the striatum precedes that in the matrix compartment and the MSP neurons of the dorsomedial caudate nucleus degenerate before those in the ventral lateral putamen. The enkephalin positive striatopallidal MSP neurons are also more vulnerable than the substance P/dynorphin MSP neurons.

We review the potential causes of this selective vulnerability of striatopallidal neurons and discuss the roles of endogenous glutamate, nitric oxide and calcium binding proteins. It is concluded that MSP neurons in general are especially susceptible to disruptions of cellular respiration due to the enormous amount of energy they expend on maintaining unusually high transmembrane potentials.

We go on to consider a subpopulation of enkephalinergic striatopallidal neurons in the rat which are particularly vulnerable. This subpopulation of neurons readily undergo apoptosis in response to experimental manipulations which affect dopamine and/or corticosteroid levels. We speculate that the cellular mechanisms underlying this cell death may also operate in degenerative disorders such as Huntington's disease thereby imposing an additional level of selectivity on the pattern of degeneration.

The possible contribution of the selective death of striatopallidal neurons to a number of clinically important psychiatric conditions including obsessive compulsive disorders and Tourette's syndrome is also discussed.

Section snippets

Abbreviations

AOAAAmino-oxyacetic acid
BDNFBrain derived neurotrophic factor
bFGFBasic fibroblast growth factor
DHEASDehydroepiandrosterone sulphate
EAAExcitatory amino acid
MPTP1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MSPMedium spiny neuron
NADPHNicotinamide adenine dinucleotide phosphate
NGFNerve growth factor
3NP3-Nitropropionic acid
NONitric oxide
NOSNitric oxide synthase
NMDAN-Methyl-d-aspartate
PCPPhencyclidine
SODSuperoxide 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.

References (285)

  • A. Bjorklund et al.

    Mechanisms of action of intracerebral neural implants: studies on nigral and striatal grafts to the lesioned striatum

    TINS

    (1987)
  • C.V. Borlongan et al.

    Behavioural pathology induced by repeated systemic injections of 3-nitropropionic acid mimics the motoric symptoms of Huntington's disease

    Brain Res.

    (1995)
  • J.J. Bouyer et al.

    Chemical and structural-analysis of the relation between cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum

    Brain Res.

    (1984)
  • J.F. Bowyer et al.

    Parenterally administered 3-nitropropionic acid and amphetamine can combine to produce damage to terminals and cell bodies in the striatum

    Brain Res.

    (1996)
  • G.D.A. Brown et al.

    Programmed cell death in the developing nervous system: a functional neural network model

    Cognitive Brain Res.

    (1994)
  • L.L. Brown et al.

    Sensory and cognitive functions of the basal ganglia

    Curr. Opin. Neurobiol.

    (1997)
  • R.E. Burke et al.

    Relative loss of the striatal striosome compartment defined by calbindin D-28K immunostaining following developmental hypoxic-ischemic injury

    Neuroscience

    (1993)
  • N.J. Butterworth et al.

    Trinucleotide (CAG) repeat length is positively correlated with the degree of DNA fragmentation in Huntington's disease striatum

    Neuroscience

    (1998)
  • J.L. Cadet et al.

    Free radicals and the pathobiology of brain dopamine systems

    Neurochem. Int.

    (1998)
  • P. Calabresi et al.

    The corticostriatal projection: from synaptic plasticity to dysfunctions of the basal ganglia

    TINS

    (1996)
  • A.G. Chapman et al.

    Excitotoxicity of NMDA and kainic acid is modulated by nigrostriatal dopaminergic fibres

    Neurosci. Lett.

    (1989)
  • Q. Chen et al.

    Cellular expression of ionotropic glutamate receptor subunits on specific striatal neuron types and its implication for striatal vulnerability in glutamate receptor-mediated excitotoxicity

    Neuroscience

    (1996)
  • X. Chen et al.

    Regional changes in c-fos expression in the basal forebrain and brain-stem during adaptation to repeated stress—correlations with cardiovascular, hypothermic and endocrine responses

    Neuroscience

    (1995)
  • N. Cheng et al.

    Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons

    Brain Res.

    (1996)
  • F. Cicchetti et al.

    Sparing of striatal neurons coexpressing calretinin and substance P (NK1) receptors in Huntington's disease

    Brain Res.

    (1996)
  • P.J. Coffey et al.

    Ibotenic acid induced demyelination in the CNS: a consequence of a local inflammatory response

    Neurosci. Lett.

    (1988)
  • C.S. Colwell et al.

    Glutamate receptor-induced toxicity in neostriatal cells

    Brain Res.

    (1996)
  • B.P. Connop et al.

    Attenuation of malonate-induced degeneration of the nigrostriatal pathway by inhibitors of nitric oxide synthase

    Neuropharmacology

    (1996)
  • A.J. Cooper et al.

    A subset of striatopallidal neurons are Fos-immunopositive following acute monoamine depletion in the rat

    Neurosci. Lett.

    (1995)
  • A.R. Crossman

    Primate models of dyskinesia—the experimental approach to the study of basal ganglia-related involuntary movement disorders

    Neuroscience

    (1987)
  • S.W. Davies et al.

    Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation

    Cell

    (1997)
  • D.L. Deupree et al.

    Studies of NMDA- and non-NMDA-mediated neurotoxicity in cultured neurons

    Neurochem. Int.

    (1996)
  • S.B. Dunnett et al.

    The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions

    TINS

    (1991)
  • D. Ebert et al.

    H-1-magnetic resonance spectroscopy in obsessive-compulsive disorder: evidence for neuronal loss in the cingulate gyrus and the right striatum

    Psychiat. Res.—Neuroimaging

    (1997)
  • A.J. Eisch et al.

    Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine

    Brain Res.

    (1992)
  • P.R. Escalona et al.

    Obsessive–compulsive disorder following bilateral globus pallidus infarction

    Biol. Psychiat.

    (1997)
  • N.B. Farber et al.

    Antipsychotic-drugs block phencyclidine receptor-mediated neurotoxicity

    Biol. Psychiat.

    (1993)
  • R.J. Ferrante et al.

    Sparing of acetylcholinesterase-containing striatal neurons in Huntington's disease

    Brain Res.

    (1987)
  • R.J. Ferrante et al.

    Excitotoxin lesions in primates as a model for Huntington's disease—histopathologic and neurochemical characterization

    Exp. Neurol.

    (1993)
  • G. Figueredo-Cardenas et al.

    Relative survival of striatal projection neurons and interneurons after intrastriatal injection of quinolinic acid in rats

    Exp. Neurol.

    (1994)
  • G. Figueredo-Cardenas et al.

    Relative resistance of striatal neurons containing calbindin or parvalbumin to quinolinic acid-mediated excitotoxicity compared to other striatal neuron types

    Exp. Neurol.

    (1998)
  • A.F. Fomina et al.

    Dexamethasone rapidly increases calcium channel subunit messenger RNA expression and high voltage-activated calcium current in clonal pituitary cells

    Neuroscience

    (1996)
  • E.D. French et al.

    Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A-10 dopamine neurons

    Neurosci. Lett.

    (1990)
  • P. Gass et al.

    Neuronal expression of AP-1 proteins in excitotoxic-neurodegenerative disorders and following nerve fiber lesions

    Prog. Neurobiol.

    (1995)
  • D.A. Abercrombie et al.

    Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens and medial frontal cortex

    J. Neurochem.

    (1989)
  • R.S. Ahima et al.

    Type I corticosteroid receptor like immunoreactivity in the rat CNS: distribution and regulation by corticosteroids

    J. Comp. Neurol.

    (1991)
  • R.L. Albin et al.

    Striatal and nigral neuron subpopulations in rigid Huntington's disease: implications for the functional anatomy of chorea and rigidity-akinesia

    Ann. Neurol.

    (1990)
  • R.L. Albin et al.

    Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington's disease

    Ann. Neurol.

    (1992)
  • G.E. Alexander et al.

    Parallel organisation of functionally segregated circuits linking basal ganglia and cortex

    Ann. Rev. Neurosci.

    (1986)
  • S.E. Andrew et al.

    The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease

    Nature Genet.

    (1993)
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