Relationship between sensorimotor gating deficits and dopaminergic neuroanatomy in Nurr1-deficient mice.
Exp Neurol
; 232(1): 22-32, 2011 Nov.
Article
em En
| MEDLINE
| ID: mdl-21820432
ABSTRACT
Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the development and maintenance of dopaminergic neurons. Reduced expression of Nurr1 has been linked to the etiopathogenesis of Parkinson's disease and other dopamine-related disorders such as schizophrenia. Recent experimental work in mice with a heterozygous constitutive deletion of Nurr1 has revealed that this genetic manipulation leads to the presence of sensorimotor gating dysfunctions in the form of reduced prepulse inhibition of the acoustic startle reflex. However, the neuronal substances for this behavioral manifestation remain essentially unknown. Since converging evidence supports a key role of the central dopamine system in the regulation of prepulse inhibition, we hypothesized that the emergence of prepulse inhibition deficits in adult Nurr1-deficient mice may be linked to dopaminergic neuroanatomical changes. To test this hypothesis, we followed a within-subject approach in which sensorimotor gating performance was correlated with post-mortem expression of several dopaminergic markers in relevant striatal and midbrain regions. We found that prepulse inhibition deficits in Nurr1-deficient mice were paralleled by reduced numbers of substantia nigra dopamine cells expressing tyrosine hydroxylase, and by decreased tyrosine hydroxylase and dopamine transporter immunoreactivity in ventral parts of the striatum. Most interestingly, we also revealed a striking negative correlation between prepulse inhibition levels and tyrosine hydroxylase immunoreactivity in Nurr1-deficient mice in dorsal striatal regions (caudate putamen) and ventral striatal regions (nucleus accumbens core and shell). Our findings thus suggest that the emergence of prepulse inhibition deficits induced by heterozygous constitutive deletion of Nurr1 is, at least in part, related to alterations in presynaptic components of the striatal dopamine system. The constellation of neuroanatomical and behavioral alterations in Nurr1-deficient mice observed here confirms previous impressions that the consequences of Nurr1 down-regulation capture neuronal and behavioral pathologies relevant especially for (but not limited to) Parkinson's disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tirosina 3-Mono-Oxigenase
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Dopamina
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Proteínas da Membrana Plasmática de Transporte de Dopamina
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Filtro Sensorial
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Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares
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Neurônios Dopaminérgicos
Limite:
Animals
Idioma:
En
Revista:
Exp Neurol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Suíça