Relationship between sensorimotor gating deficits and dopaminergic neuroanatomy in Nurr1-deficient mice.

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.

Vuillermot S ，Feldon J ，Meyer U 《-》

Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency.

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the dopaminergic development and survival. Altered expression of Nurr1 has been suggested as a potential genetic risk factor for dopamine-related brain disorders, including schizophrenia. In support of this, recent experimental work in genetically modified mice shows that mice with a heterozygous constitutive deletion of Nurr1 show a facilitation of the development of schizophrenia-related behavioral abnormalities. However, the behavioral characterization of this Nurr1-deficient mouse model remains incomplete. This study therefore used a comprehensive behavioral test battery to evaluate schizophrenia-relevant phenotypes in Nurr1-deficient mice. We found that these mice displayed increased spontaneous locomotor activity and potentiated locomotor reaction to systemic treatment with the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). In addition, male but not female Nurr1-deficient mice showed significant deficits in the prepulse inhibition and prepulse-elicited reactivity. However, Nurr1 deletion did not induce overt abnormalities in other cardinal behavioral and cognitive functions known to be impaired in schizophrenia, including social interaction and recognition, spatial recognition memory or discrimination reversal learning. Our findings thus suggest that heterozygous constitutive deletion of Nurr1 results in a restricted phenotype characteristic of schizophrenia symptomatology, which primarily relates to motor activity, sensorimotor gating and responsiveness to the psychomimetic drug MK-801. This study further emphasizes a critical role of altered dopaminergic development in the precipitation of specific brain dysfunctions relevant to human psychotic disorder.

Vuillermot S ，Joodmardi E ，Perlmann T ，Ove Ögren S ，Feldon J ，Meyer U ... -  《-》

Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.

Inflammation-induced disruption of fetal neurodevelopmental processes has been linked to the precipitation of long-lasting behavioral abnormalities and associated neuropathology. Recent longitudinal investigations in prenatal immune activation models have revealed developmental correspondences between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Two examples of such developmental correspondences are increased expression of the orphan nuclear receptor Nurr1 (NR4A2) in ventral midbrain areas and disruption of prepulse inhibition of the acoustic startle reflex, with both the neuroanatomical and behavioral effects emerging only in adult but not pre-pubertal subjects exposed to prenatal maternal inflammation. In the present study, we tested the hypothesis that Nurr1 may be a critical molecular mediator of prepulse inhibition deficits induced by prenatal immune activation. To this end, we compared the effects of prenatal immune challenge on adult PPI in wild-type (wt) mice and mice with a heterozygous constitutive deletion of Nurr1 (Nurr1+/-) using a well established mouse model of maternal immune activation by exposure to the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid). We found that prenatal poly(I:C) treatment on gestation day 9 was similarly effective in disrupting prepulse inhibition in adult wt and Nurr1+/- mice. Prenatal poly(I:C) treatment also generally increased midbrain Nurr1-positive cells and counteracted the genetically driven Nurr1 deficit in the substantia nigra. Our data thus suggest that at least under the present experimental conditions, Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.

Vuillermot S ，Feldon J ，Meyer U 《-》

Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury.

Le W ，Conneely OM ，He Y ，Jankovic J ，Appel SH ... -  《-》

Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra.

Nuclear receptor-related factor 1 (Nurr1), a member of the nuclear receptor superfamily, is associated with the induction of dopaminergic (DA) phenotypes in developing and mature midbrain neurons. It is well established that dopaminergic nigrostriatal function decreases with age. Whether age-related deficits in DA phenotypic markers are associated with alterations in Nurr1 expression is unknown. The present study found that virtually all of tyrosine hydroxylase-immunoreactive (TH-ir) neurons within the young adult human substantia nigra were Nurr1-immunoreactive (Nurr1-ir) positive. Stereologic counts revealed a significant reduction in the number of Nurr1-ir nigral neurons in middle-aged (23.13%) and aged (46.33%) individuals relative to young subjects. The loss of Nurr1-ir neurons was associated with a similar decline in TH-ir neuron number. In this regard, TH-ir neuronal number was decreased in middle-aged (11.10%) and in aged (45.97%) subjects, and this loss of TH-ir neurons was highly correlated (r = 0.92) with the loss of Nurr1-ir neurons. In contrast, the number of melanin-containing nigral neuron number was generally stable across age groups, indicating that changes in Nurr1 and TH reflect phenotypic age-related changes and not frank neuronal degeneration. In support of this concept, confocal microscopic analyses of Nurr1-ir and TH-ir fluorescence intensity revealed parallel decreases in Nurr1- and TH-immunofluorescence as a function of age. These data demonstrate that age-related decline of DA phenotypic markers is associated with down-regulation of Nurr1 expression in the SN.

Chu Y ，Kompoliti K ，Cochran EJ ，Mufson EJ ，Kordower JH ... -  《JOURNAL OF COMPARATIVE NEUROLOGY》