Neonatal dopamine depletion induces changes in morphogenesis and gene expression in the developing cortex.
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.
Krasnova
Irina N
IN
Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, National Institutes of Health/DHHS, Bethesda, MD 20892, USA.
Betts
Elizabeth S
ES
Dada
Abiola
A
Jefferson
Akilah
A
Ladenheim
Bruce
B
Becker
Kevin G
KG
Cadet
Jean Lud
JL
Hohmann
Christine F
CF
D000818:Animals; D000831:Animals, Newborn; D003342:Corpus Striatum / Q000254:growth & development / Q000502:physiology; D003714:Denervation; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity; D020411:Oligonucleotide Array Sequence Analysis; D016627:Oxidopamine / Q000633:toxicity; D016548:Prosencephalon / Q000254:growth & development* / Q000502:physiology*; D012018:Reflex; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013565:Sympatholytics / Q000633:toxicity
D013565:Sympatholytics; D016627:Oxidopamine; D004298:Dopamine