Retinoic Acid Synthesis in the Postnatal Mouse Brain Marks Distinct Developmental Stages and Functional Systems

Abstract

Retinoic acid (RA) affects development and function of the brain, but little is known about how much is made locally and where it is distributed. To identify RA-sensitive neural processes, we mapped the RA-synthesizing retinaldehyde dehydrogenases (RALDHs) during postnatal brain formation of the mouse. High and stable RALDH expressions mark the basal ganglia, olfactory bulbs, hippocampus and auditory afferents as major sites of RA actions in the functional brain. During the early postnatal period, transient and very high RALDH3 expressions distinguish two developmental events: (i) the colonization of the nucleus accumbens and the olfactory bulbs by neuronal precursors and (ii) the maturation of selected parts of the cerebral cortex. In the cortex, RALDH3 is transiently activated in postmigratory layer II/III neurons during formation of their dendritic arbors and it is transported in their axons across the corpus callosum. RALDH3-expressing cortical regions include most of the limbic lobe, with strongest expression in the anterior cingulate cortex, medial and lateral secondary visual cortices, auditory cortical areas, the secondary motor cortex and some association areas. The transient cortical expression points to a brief RA-critical period during differentiation of the cortical network that serves in the coordination of sensory-motor activity with emotional and recently learned information.

The neurobiology of retinoic acid in affective disorders

“…Recent quantitation of RA concentrations in the adult brain found that the striatum showed the highest levels in the brain (Kane et al 2005). The source of RA synthesis for the dorsal striatum and nucleus accumbens is presumed to be the synthetic enzyme RALDH1, which is present in the dopaminergic terminals that innervate the striatum from the ventral tegmental area (McCaffery and Drager 1994;Wagner et al 2002). Thus, the striatum and nucleus accumbens are regions where RA may be supplied in a similar fashion to that of dopamine -by transfer of the synthetic enzyme along terminals from the ventral tegmental area that innervate the striatum and nucleus accumbens.…”

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

“…For example, the RA-synthesizing retinaldehyde dehydrogenase enzymes are poorly expressed in the fully developed striatum (Wagner et al, 2002). The cellular retinal-binding proteins (CRBP) are not expressed in the striatum of adult rodents and the cellular retinoic acid-binding protein (CRABP) is only expressed in cholinergic neurons of the striatum and not in medium spiny neurons (Zetterström et al, 1999).…”

Effects of retinoic acid on ischemic brain injury-induced neurogenesis

“…Retinoid binding proteins are expressed in olfactory bulb and lateral ventricle ependyma (Zetterstrom et al, 1994(Zetterstrom et al, , 1999, and RA receptors persist into adulthood in the olfactory bulb (Krezel et al, 1999). The RA synthesizing enzyme retinaldehyde dehydrogenase-3 (RALDH3) is expressed in the SVZ, RMS and olfactory glomerular layer (Wagner et al, 2002). Importantly, adult transgenic mice expressing a RA response element (RARE)-reporter construct showed reporter expression in the SVZ and olfactory granular and glomerular layers, indicating RA-induced transcriptional activation in this pathway (Thompson et al, 2002).…”