| 2005 |
Prog Neurobiol. 2005 Mar;75(4):275-93. |
Lane MA, Bailey SJ. |
Role
of retinoid signalling in the adult brain. |
Much of the research conducted on retinoid
signalling in the nervous system has focussed on developmental effects
in the embryonic or early postnatal brain. Here, we review the increasing
body of evidence indicating that retinoid signalling plays an important
role in the function of the mature brain. Components of the metabolic
pathway for retinoids have been identified in adult brain tissues,
suggesting that all-trans-retinoic acid (ATRA) can be synthesized
in discrete regions of the brain. The distribution of retinoid receptor
proteins in the adult nervous system is different from that seen during
development; and suggests that retinoid signalling is likely to have
a physiological role in adult cortex, amygdala, hypothalamus, hippocampus,
striatum and associated brain regions. A number of neuronal specific
genes contain recognition sequences for the retinoid receptor proteins
and can be directly regulated by retinoids. Disruption of retinoid
signalling pathways in rodent models indicates their involvement in
regulating synaptic plasticity and associated learning and memory
behaviours. Retinoid signalling pathways have also been implicated
in the pathophysiology of Alzheimer's disease, schizophrenia and depression.
Overall, the data underscore the likely importance of adequate nutritional
Vitamin A status for adult brain function and highlight retinoid signalling
pathways as potential novel therapeutic targets for neurological diseases. |
| 2004 |
The NeuroScientist 10(5):409-421 |
Mey
J et al |
Mey J, McCaffery
P. Neuroscientist. 2004 Oct;10(5):409-21 |
Isotretinoin is a very effective medication for the
treatment of severe recalcitrant acne. Excellent review on Retinoic
Acid Signalling. Section on 'Retinoic Acid in Learning and Neural
Plasticity' (pg 410) and section on 'RA functions in the hippocampus
- A potential role in Neurogenesis and Depression'. |
| 2004 |
Ann N Y Acad Sci. Jun;1021:436-40 |
Sakai
Y et al |
Sakai Y, Crandall
JE, Brodsky J, McCaffery P.13-cis Retinoic acid (accutane) suppresses
hippocampal cell survival in mice.Ann N Y Acad Sci. 2004 Jun;1021:436-40. |
: We now show,
in a mouse model, that endogenous RA generated by synthetic enzymes
in the meninges acts on hippocampal granule neurons, and chronic (3-week)
exposure to a clinical dose of 13-cis RA may result in hippocampal
cell loss. In humans this may be conjectured to be the mechanism by
which Accutane contributes to depression. |
| 2004 |
Proc Natl Acad Sci U S A. Apr 6;101(14):5111-6 |
Crandall
J et al |
Crandall
J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery P (2004)
13-cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent
learning in mice. Proceedings of the National Academy of Sciences
USA 101:5111-5116 |
This report demonstrates that a clinical dose (1 mg/kg/day) of 13-cis-RA
in mice significantly reduces cell proliferation in the hippocampus
and the subventricular zone, suppresses hippocampal neurogenesis,
and severely disrupts capacity to learn a spatial radial maze task.
The results demonstrate that the regions of the adult brain where
cell proliferation is ongoing are highly sensitive to disruption by
a clinical dose of 13-cis-RA. |
| 2004 |
Program No. 437.15. 2004 Abstract Viewer/Itinerary Planner.
Washington, DC: Society for Neuroscience, 2004. Online. |
S.A. Ferguson, F.J. Cisneros, J.P. Hanig, B. Gough,
K.J. Berry. |
CHRONIC ORAL ACCUTANE (ACC), BUT NOT ALL-TRANS-RETINOIC
ACID (ATRA), TREATMENT CAUSES BEHAVIORAL ALTERATIONS IN THE FORCED
SWIM TEST |
The anti-acne drug, ACC (isotretinoin, 13-cis-retinoic
acid), is associated with depression, suicide ideation and suicide.
The potential confounds inherent in human research necessitated the
current animal study. Here, male and female Sprague-Dawley rats (n=6/sex/dose)
were gavaged with 0 (soy oil), 7.5, or 22.5 mg/kg/day ACC beginning
on postnatal day 82. Previous work indicates that 7.5 mg/kg produces
blood ACC levels similar to those of humans taking recommended ACC
doses (1 mg/kg/day). As a comparison for in vivo isomerization of
ACC, separate groups of rats were gavaged with 10 or 15 mg/kg/day
ATRA (n=6/sex/dose). After 7 weeks of chronic treatment, a forced
swim test was conducted on two consecutive days. Each rat was placed
in an inescapable cylindrical tank of 25oC water for 10 (day 1) or
5 (day 2) min. Tests began ~ 1 hour post-gavage. Dive frequency and
durations of active swimming, immobility (including floating), and
climbing/struggling were measured. Neither ACC nor ATRA altered diving
or swim durations. ATRA treatment had no effect on any other measured
behavior. However, rats treated with 7.5 mg/kg ACC engaged in longer
durations of climbing/struggling and shorter durations of immobility
than controls (p<.05). This ACC treatment effect did not interact
with test session (day) or sex, although there were significant main
effects of session and sex, and the effect was not caused by alterations
in locomotor activity (see accompanying abstract for lack of open
field activity changes). In general, short immobility and long climb/struggle
durations are indications of decreased depression (i.e., antidepressant
treatment shortens immobility time). Thus, ACC doses which produce
blood levels similar to humans cause behavioral alterations in a rodent
assessment designed to assess depression. |
| 2003 |
Behav Brain Res. 2003 Oct 17;145(1-2):37-49. |
Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret
P, Jaffard R. |
Vitamin A deficiency and relational memory deficit in
adult mice: relationships with changes in brain retinoid signalling. |
Vitamin A and its derivatives, the retinoids, have recently
been reported to be implicated in the synaptic plasticity of the hippocampus
and in cognitive functions. Acting via transcription factors, retinoids
can regulate gene expression via their nuclear receptors [retinoic
acid receptors (RARs) and retinoid X receptors (RXRs)]. We recently
showed that a moderate (about 30%) hypoexpression of brain (and hippocampal)
retinoid signalling, like that naturally occurring in the aged brain
of mice, might be related to a selective relational memory deficit.
To further assess this hypothesis, the present study investigated
the effects of Vitamin A deprivation of varying duration both on the
brain expression of retinoid receptors (RARbeta and RXRbeta/gamma)
and two associated target genes [tissue-type transglutaminase (tTG)
and neurogranin, (RC3)], and on radial maze discrimination learning
using young adult mice as subjects. We observed that irrespective
of its duration (i.e. 31 or 39 weeks), Vitamin A deprivation resulted
in a significant reduction (25-30%) in the expression of brain RARbeta,
RXRbeta/gamma and tTG mRNAs. Conversely, only the 39-week condition
was found to induce a significant decrease in brain RC3 mRNAs contents
and a selective relational memory impairment. Finally, daily administration
of retinoic acid (RA) failed to reverse the 39-week Vitamin A deficiency
(VAD)-related cognitive deficit and to fully normalise the associated
brain retinoid hyposignalling. In particular, there was no evidence
for an up-regulating effect of RA on whole brain (and hippocampal)
RC3 mRNAs of the 39-week-depleted mice. The results show that post-natal
VAD may induce a selective memory impairment and give further support
to the hypothesis that the fine regulation of retinoid-mediated gene
expression is important for optimal brain functioning and higher cognition. |
| 2003 |
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2901-5 |
Goodman AB, Pardee AB. |
Evidence
for defective retinoid transport and function in late onset Alzheimer's
disease |
The hypothesis of this article is that
late onset Alzheimer's disease (AD) is influenced by the availability
in brain of retinoic acid (RA), the final product of the vitamin A
(retinoid) metabolic cascade. Genetic, metabolic, and environmental/dietary
evidence is cited supporting this hypothesis. Significant genetic
linkages to AD are demonstrated for markers close to four of the six
RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3,
retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of
the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading
cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. Synthesis
of the evidence supports retinoid hypofunction and impaired transport
as contributing factors. These findings suggest testable experiments
to determine whether increasing the availability of retinoid in brain,
possibly through pharmacologic targeting of the RA receptors and the
cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid
plaque formation. |
| 2002 |
NIMH
meeting in 2002 entitled "Functional Effects of Retinoids in the Adolescent
and Adult Central Nervous System" |
Click
here for link...Baselines studies examining the effects of a range
of retinoid doses and routes of admisinstration on neurochemical measures
in models assessing mood, anxiety, aggression, implusivity and cognitive
function..... |
| 2000 |
Neuron, 27, 359-370 |
Mello, CV et al (New York) |
Site-Specific Retinoic Acid Production in
the Brain of Adult Songbirds |
They found conclusive evidence for localized
retinoic acid synthesis in an adult vertebrate brain and indicate
that the retinoic acid-generating system plays a significant role
in the maturation of a learned behaviour. The main implication is
that processes under retinoid control appear to extend beyond the
embryonic period into adulthood and affect the organisation of brain
circuitry and behaviour. |
| 1998 |
Proc. Natl. Acad. Sci, 95, 7240-7244. |
Goodman, AB |
Three independent lines of evidence suggest retinoids
as causal to schizophrenia |
Three lines of evidence are suggested, which include
(i)anomalies similar to those caused by retinoid dysfunction are found
in schizophrenia and their relatives (ii) loci suggested to be linked
to schizophrenia candidate genes regulated by retinoic acid and (iii)
transcriptional activation of the dopamine receptor and numerous schizophrenia
genes is regulated by retinoic acid. |
| 1998 |
Proc. Natl. Acad. Sci, 95, 7240-7244. |
Goodman, AB |
Three independent lines of evidence suggest retinoids
as causal to schizophrenia |
Three lines of evidence are suggested, which include
(i)anomalies similar to those caused by retinoid dysfunction are found
in schizophrenia and their relatives (ii) loci suggested to be linked
to schizophrenia candidate genes regulated by retinoic acid and (iii)
transcriptional activation of the dopamine receptor and numerous schizophrenia
genes is regulated by retinoic acid. |
| 1998 |
Science.279, 836-867 |
Chambon et al: |
Impaired Locomotion and Dopamine Signaling in Retinoid
Receptor Mutant Mice. |
The authors demonstrated that retinoic acid are involved
in the regulation of brain functions in adult murine brain. They also
suggest that retinoic acid signalling defects may contribute to pathologies
such as Parkinsons disease and schizophrenia. It clearly supports
the involvement of retinoic acid in dopaminergic signalling. |
| 1995 |
Am. J Med Gen, 60:335-348. |
Goodman AB: |
Chromosomal locations and modes of action of genes of
the retinoid (Vitamin A) system support their involvement in the etiology
of schizophrenia. |
This is a very important published study which sets
out evidence of an association of retinoids in schizophrenia, comes
from the recent discovery that genes of the retinoid system lie in
very close proximity to candidate schizophrenia genes and it has been
postulated that there is an increase likelihood that these schizophrenia
genes are regulated by retinoids, due to this close chromosomal proximity. |
| 1994 |
Nueroscience, 62, 899-918 |
Olson et al (Sweden) |
Localization of Cellular Retinoid-Binding Proteins Suggests
Specific Roles for Retinoids in the Adult Central Nervous System. |
The authors find a widespread presence of two retinoic
binding proteins in the brain and spinal cord of the adult rat, which
suggest that retinoids have important roles of gene expression in
normal brain function. Based on evidence from this study as well as
other studies relating to the presence of these CRBP proteins in newborn,
the authors suggest that the proteins are involved in processes of
nerve growth and development as well as in adult neuronal plasticity. |
