Role of retinoids in the CNS: differential expression of retinoid binding proteins and receptors and evidence for presence of retinoic acid

Abstract

Retinoic acid (RA), a retinoid metabolite, acts as a gene regulator via ligand-activated transcription factors, known as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both existing in three different subtypes, alpha, beta and gamma. In the intracellular regulation of retinoids, four binding proteins have been implicated: cellular retinol binding protein (CRBP) types I and II and cellular retinoic acid binding protein (CRABP) types I and II. We have used in situ hybridization to localize mRNA species encoding CRBP- and CRABP I and II as well as all the different nuclear receptors in the developing and adult rat and mouse central nervous system (CNS), an assay to investigate the possible presence of RA, and immunohistochemistry to also analyse CRBP I- and CRABP immunoreactivity (IR). RXRbeta is found in most areas while RARalpha and -beta and RXRalpha and -gamma show much more restricted patterns of expression. RARalpha is found in cortex and hippocampus and RARbeta and RXRgamma are both highly expressed in the dopamine-innervated areas caudate/putamen, nucleus accumbens and olfactory tubercle. RARgamma could not be detected in any part of the CNS. Using an in vitro reporter assay, we found high levels of RA in the developing striatum. The caudate/putamen of the developing brain showed strong CRBP I-IR in a compartmentalized manner, while at the same time containing many evenly distributed CRABP I-IR neurons. The CRBP I- and CRABP I-IR patterns were closely paralleled by the presence of the corresponding transcripts. The specific expression pattern of retinoid-binding proteins and nuclear retinoid receptors as well as the presence of RA in striatum suggests that retinoids are important in many brain structures and emphasizes a role for retinoids in gene regulatory events in postnatal and adult striatum.

The neurobiology of retinoic acid in affective disorders

“…The RA receptors are widely distributed in the adult brain (Krezel et al 1999;Zetterstrom et al 1999;Zetterström et al 1994) which would suggest that RA is necessary for tasks throughout the brain. However, RA itself is much less widely distributed (Mey and McCaffery 2004) and, if the RA receptors are bound to RAREs without ligand, as described in section 2.2, then they may act to repress transcription.…”

“…This deactivation of the RA signaling system is not due to restricted amounts of RA however, since injections of RA into the reporter mouse do not activate the reporter in regions in which it is not already expressed (Luo et al 2004b), thus this loss of responsiveness is presumably at a genomic level. Regions of the brain that exhibit RA signaling as determined using RA reporter mice include the limbic system, in particular the hippocampus (section 2.4) (Krezel et al 1999;Luo et al 2004b;Misner et al 2001;Sakai et al 2004;Zetterstrom et al 1999) as well as the medial prefrontal cortex including prefrontal and cingulate cortex and retrosplenial area together with subregions of the thalamus and hypothalamus (Luo et al 2004b). One suggested common feature of several of the regions of RA signaling is that these are areas of high neuronal plasticity (McCaffery et al 2006;Thompson Haskell et al 2002).…”

“…Null mutation of RAR beta results in loss of LTP and LTD as well as deficits in a spatial learning task (Chiang et al 1998). Confounding the interpretation of this result though is the lack of expression of RAR beta in the mouse hippocampus (Krezel et al 1999;Zetterstrom et al 1999). Since these null mutants are not conditional, the effect of receptor loss may be during development of the hippocampus.…”

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

“…Additional investigations are needed in order to identify the cellular The present results also indicate that retinoids might be involved in behavioral and biochemical effects of neuroleptics. The RXRg1 isoform is by far the most abundant retinoid receptor expressed in the adult StDL (Zetterström et al, 1999;Langlois et al, 2001) and therefore, the effects of retinoid ligands are likely mediated through interaction with this receptor isoform. We show here that haloperidol administration strongly increase the percentage of colocalization of NGFI-B and RXRg1 transcripts in the striatum.…”

“…Several lines of evidence strongly suggest that in addition to have a key role during development, retinoic acid might have an important role in dopamine-innervated basal ganglia in the mature brain. Both RARb and RXRg isoforms are expressed in the striatum, nucleus accumbens and olfactory tubercle of both newborn and adult rats (Krezel et al, 1999;Saga et al, 1999;Zetterström et al, 1999). It has been shown that RARb-and RXRg-deficient mice demonstrate impaired locomotion, dopamine signaling (Krezel et al, 1999) and an altered response to dopamine antagonists (Saga et al, 1999).…”