Neonatal dopamine depletion induces changes in morphogenesis and gene expression in the developing cortex

Abstract

The mesocorticolimbic dopamine (DA) system is implicated in mental health disorders affecting attention, impulse inhibition and other cognitive functions. It has also been involved in the regulation of cortical morphogenesis. The present study uses focal injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of BALB/c mice to examine morphological, behavioral and transcriptional responses to selective DA deficit in the fronto-parietal cortex. Mice that received injections of 6-OHDA on postnatal day 1 (PND1) showed reduction in DA levels in their cortices at PND7. Histological analysis at PND120 revealed increased fronto-cortical width, but decreased width of somatosensory parietal cortex. Open field object recognition suggested impaired response inhibition in adult mice after 6-OHDA treatment. Transcriptional analyses using 17K mouse microarrays showed that such lesions caused up-regulation of 100 genes in the cortex at PND7. Notably, among these genes are Sema3A which plays a repulsive role in axonal guidance, RhoD which inhibits dendritic growth and tubulin beta-5 microtubule subunit. In contrast, 127 genes were down-regulated, including CCT-epsilon and CCT-zeta that play roles in actin and tubulin folding. Thus, neonatal DA depletion affects transcripts involved in control of cytoskeletal formation and pathway finding, instrumental for normal differentiation and synaptogenesis. The observed gene expression changes are consistent with histological cortical and behavioral impairments in the adult mice treated with 6-OHDA on PND1. Our results point towards specific molecular targets that might be involved in disease process mediated by altered developmental DA regulation.

Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: Persisting effects on locomotor activity, learning and nicotine self-administration

“…It is possible that while there are relatively the same number of dopaminergic neurons in control and 6-OHDA-treated rats, 6-OHDA-treated rats do not have the proper synapse structure for normal functioning. This is supported by anatomical changes observed in the adult mouse brain after neonatal 6-OHDA lesioning (Krasnova et al 2007). Lastly, a combination of these two models could account for the long-term effects of 6-OHDA lesioning.…”

“…Most important was the up-regulation of genes involved in the repulsion of axon guidance and genes that inhibit the growth of dendrites and microtubule formation (Krasnova et al 2007). In addition, genes necessary for tubulin and actin folding were found to be down-regulated (Krasnova et al 2007). In the context of this model, it is possible that while there is a full recovery of relative dopamine levels, there are altered morphological and structural defects in adulthood.…”

Aminochrome Induces Disruption of Actin, Alpha-, and Beta-Tubulin Cytoskeleton Networks in Substantia-Nigra-Derived Cell Line

“…The cyanobacterial toxin Microcystin-LR induces apoptotic shrinkage associated with the shortening and loss of actin filaments, associated with a concentration-dependent depolymerization of microtubules (Gácsi et al 2009). Dopamine depletion induced by 6-hydroxydopamine affects transcripts involved in control of cytoskeletal formation (Krasnova et al 2007). Also, dopamine induces supernumerary centrosomes and subsequent cell death (Diaz-Corrales et al 2008).…”

Monoamine Oxidases Regulate Telencephalic Neural Progenitors in Late Embryonic and Early Postnatal Development

“…Brain samples were homogenized in 0.01 m HClO 4 and centrifuged at 14,000 g for 15 min. NE, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-HT, and 5-hydroxyindoleacetic acid (5-HIAA) levels were analyzed in the brain extracts using HPLC with electrochemical detection, as described previously (Ladenheim et al, 2000; Krasnova et al, 2007; Martin et al, 2007). The protein concentrations were determined using the BCA kit (Pierce).…”