Immunocytochemical expression of dopamine‐related transcription factors Pitx3 and Nurr1 in prenatally stressed adult rats

Abstract

Rats exposed to different types of stress during the last week of pregnancy produce offspring that show severe anomalies in neural development and brain morphology. We have previously reported that prenatal stress (PS) induced by immobilization increases D2-type dopamine (DA) receptor levels in the adult offspring, with a concomitant reduction in DA release in prefrontal cortex after amphetamine stimulation. Recently, two transcription factors, Nurr1 and Pitx3, have been identified that are expressed at critical moments of DA neuron differentiation. Their genetic expression is activated immediately after these neuron determinations and maintained through adult life. Nurr1 regulates several proteins that are required for dopamine synthesis and regulation, and Pitx3 is specifically involved in the terminal differentiation and maintenance of dopamine neurons. By means of an immunocytochemistry approach, we studied the expression of Nurr1 and found an ubiquitous distribution in cerebral cortex, hippocampus, thalamus, amygdala, and midbrain, whereas Pitx3 remains restricted to the mesencephalic DA neurons such as substantia nigra and ventral tegmental area. Our results show that the expression of both Nurr1 and Pitx3 increased in prenatally stressed adult offspring in the ventral tegmental area, whereas no changes were observed in the substantia nigra area. It might be hypothesized that the increase of the specific dopaminergic transcription factors might be a compensatory mechanism to counteract the reduction in dopamine levels previously observed as a consequence of prenatal stress.

Schizophrenia-Like Features in Transgenic Mice Overexpressing Human HO-1 in the Astrocytic Compartment

“…The GFAP.HMOX1 mouse teaches that sustained or repeated induction of HO-1 in brain astrocytes may be a critical link in the etiopathogenesis of schizophrenia and other neurodevelopmental disorders by transducing the deleterious influences of various perinatal stressors into altered patterns of dopaminergic cell development in the immature subcortex. Our findings suggest further that enhanced Nurr1 and Pitx3 expression recently reported in the brains of prenatally stressed adult rats (Katunar et al, 2009) may have been contingent on the antecedent upregulation of HO-1 in exposed astroglia. As postulated for human schizophrenia (Grace, 2000), a prenatal window of astroglial stress appears necessary for the delayed emergence of DA-dependent hyperlocomotion in our model because the latter did not materialize when glial expression of the HMOX1 transgene was selectively repressed by Dox in the prepubertal period.…”

“…The latter likely result from enhanced expression of TH and DAT mRNA and protein in these brain regions. The registered induction of Nurr1 and Pitx3, transcription factors required for dopamine synthesis/regulation and terminal differentiation/maintenance of dopaminergic neurons, respectively, would account for the upregulation of TH and DAT in these animals (Katunar et al, 2009). In turn, suppression of miR-133b (Kim et al, 2007) and miR-145 in the basal ganglia of GFAP.HMOX1 would explain the upregulation of Pitx3 and Nurr1 in the affected striatum and substantia nigra.…”

“…In addition, both nurr1 and pitx3 proteins (measured by ELISA) in the transgenic SN/VTA, but not STM, were significantly elevated at 48 weeks compared with WT littermates ( p Ͻ 0.05). Pitx3 protein concentrations were below detection level in WT and TG STM, reflecting the fact that, unlike nurr1, pitx3 elaboration remains restricted to mesencephalic DA neurons (Katunar et al, 2009) (Fig. 4 D).…”

Differential neuronal changes in medial prefrontal cortex, basolateral amygdala and nucleus accumbens after postweaning social isolation

“…The number (19,730 ± 2,442.7 TH-positive VTA neurons, unilateral count) is close to previous findings in adult male Sprague-Dawley (SD) rats (Nair-Roberts et al 2008;Johnson et al 2010). Some DA-related transcription factors and number of TH-positive neurons are sensitive to prenatal stress and maternal malnutrition (Katunar et al 2009;Katunar et al 2010;Vucetic et al 2010), indicating the critical time window for the development of midbrain DA neuron is in the prenatal period (Meyer and Feldon 2009). The number and density of VTA TH-positive neurons are therefore not responsive to postweaning life events.…”

Ontogenetic Expression of Dopamine-Related Transcription Factors and Tyrosine Hydroxylase in Prenatally Stressed Rats

“…The expression of both Nurr1 and Pitx3 increased in PS adult offspring in the VTA area, whereas no changes were observed in SN areas (Katunar et al 2009). …”