Abstract presented at the Winter
Workshop on Schizophrenia Research, Davos, Switzerland, 2002
McGrath J, Eyles D, Mowry B, Yolken R, Buka S (2002).
Low maternal vitamin D as a risk factor for schizophrenia: a pilot
study using banked sera. Schizophrenia Research 53. 228.
LOW MATERNAL VITAMIN D AS A RISK
FACTOR FOR SCHIZOPHRENIA: A PILOT STUDY USING BANKED SERA
J McGrath, D Eyles, B Mowry, R Yolken, S Buka
Queensland Centre for Schizophrenia Research, The Park, Centre for
Mental Health - Treatment, Research and Education, Wacol, 4076 QLD
Australia. john@wph.uq.edu.au
Background
Based on epidemiological features of schizophrenia, it has been
proposed that low maternal vitamin D may be a risk-modifying factor
for schizophrenia.
Method
The level of 25-hydroxyvitamin D was assayed in sera drawn during
the third trimester of (a) mothers of individuals with schizophrenia
or schizoaffective disorders and (b) mothers of unaffected controls.
The subjects were drawn from the National Collaborative Perinatal
Project. There were a total of 26 cases and 51 controls. For 25
of the cases, we matched two controls based on race, gender of offspring
and date of birth, while for one case, sera from only one matched-control
was available.
Results
Based on all subjects (cases and controls), vitamin D levels were
(a) significantly lower in winter versus other seasons and (b) significantly
lower in blacks versus whites. However, there was no significant
difference in vitamin D levels between cases and controls. Within
the black subgroup (7 cases and 14 controls), there was a trend
level difference (p=0.06) in the predicted direction, with the mothers
of cases having very low levels of vitamin D.
Discussion
The results allow us to reject the hypothesis that prenatal vitamin
D operates as a continuous graded risk factor for schizophrenia
within its full range of values. The finding for the black subgroup
raises the possibility that below a certain critical threshold,
the exposure may be associated with an increased risk of schizophrenia.
This revised hypothesis needs to be tested in a larger sample.
The Stanley Foundation supported this project.
Mackay-Sim A, Feron F, Eyles D, Brown J, McGrath (2002). Low vitamin
D disrupts prepulse inhibition in adult but not young rats: a new
animal model of schizophrenia. Schizophrenia Research 53, 216.
DW Eyles, F Feron, J Brown, A Mackay-Sim, J McGrath
Queensland Centre for Schizophrenia Research, The Park, Centre for
Mental Health - Treatment, Research and Education, Wacol, Qld 4076
Australia Eyles@plpk.uq.edu.au
Low prenatal vitamin D has recently been proposed
as a candidate risk-modifying factor for schizophrenia (McGrath,
1999). To date, the biological plausibility of this candidate has
rested on the data showing that (a) vitamin D receptors are present
in the developing brain, (b) vitamin D induces NGF and the low affinity
neurotrophin receptor P75 in vitro and (c) vitamin D is a potent
antimitotic/prodifferentiation agent. Here we present the findings
from an experiment comparing the brains of new born pups from vitamin
D depleted versus control dams. Brains from vitamin D deplete neonates
had proportionally thinner corticies and larger lateral ventricles
(P <0.02 n =12). The rate of cellular mitosis was elevated in
the dentate gyrus and the hypothalamus (P<0.001 and P<0.05
respectively) with a nonsignificant trend towards diminished apoptosis
observed in all brain regions examined. Neonatal NGF levels were
also decreased (P<0.02). These data indicate that a decreased
prenatal vitamin D is associated with altered brain development.
While the mechanisms underlying these changes are still unclear,
it appears that vitamin D3 is required to retard cellular proliferation
and promote cellular differentiation in the brain. Maternal vitamin
D3 levels may therefore play an important and previously unrecognised
role in foetal brain development.
J McGrath. Hypothesis: is low prenatal vitamin D a
risk-modifying factor for schizophrenia? Schiz Res 40: 173-177,
1999.
Eyles D, Burkert R, McGrath J (2002). Vitamin D3 regulates the low
affinity neurotrophin receptor p75 in the developing rat brain.
Schizophrenia Research 53. 228.
VITAMIN D3 REGULATES THE LOW AFFINITY
NEUROTROPHIN RECEPTOR p75 IN THE DEVELOPING RAT BRAIN.
DW Eyles, R Burkert, J McGrath
Queensland Centre for Schizophrenia Research, The Park, Centre for
Mental Health - Treatment, Research and Education, Wacol, Qld 4076
Australia. Eyles@plpk.uq.edu.au
Evidence is emerging that vitamin D3 may play a role in brain development
(McGrath et al, 2001). For example, receptors for the vitamin are
present in differentiating fields of the developing brain, and synthesis
of the active form of the vitamin occurs in glial cells. Vitamin
D3 has also been implicated in the regulation of the low-affinity
neurotrophin receptor (p75) in peripheral neurons, a fact that may
be crucial to their survival during development. However, little
is known about the impact of vitamin D3 on p75 in the central nervous
system. In this study we examined the effect of vitamin D deprivation
on p75 expression in embryonic brains from maternally vitamin D
deprived rats and we also examined the impact of 1,25 dihydroxyvitamin
D3 on p75 in isolated hippocampal neurons. p75 was expressed prominently
in the basal ganglia, the infragranular portion of the developing
cortex and in certain fibre tracts in the embryonic brain. At every
embryological stage examined both immunohistochemical response and
relative transcript levels for the receptor were significantly lower
in embryos from vitamin D3 deprived dams (P<0.01). Conversely
the presence of the vitamin increased the immunochemical response
for p75 in hippocampal neurons in vitro (P<0.05). Neurotrophins
and their receptors play a prominent role in brain development and
given the regulatory control of p75 expression described here, maternal
vitamin D3 levels may be crucial in this process.
McGrath J, Feron F, Eyles D, Mackay-Sim A (2001).
Vitamin D - the neglected neurosteroid? Trends in Neuroscience,
24, 570-571.
Feron F, Mackay-Sim A, Eyles D, Brown J, McGrath J (2002). Vitamin
D depletion during development markedly alters gene expression in
adult rat brain: gene array assessment of a novel risk factor for
schizophrenia. Schizophrenia Research 53. 83.
VITAMIN D DEPLETION DURING DEVELOPMENT MARKEDLY
ALTERS GENE EXPRESSION IN THE ADULT RAT BRAIN: GENE ARRAY ASSESSMENT
OF A NOVEL RISK FACTOR FOR SCHIZOPHRENIA.
F Feron, A Mackay-Sim , D Eyles, J Brown, J McGrath
Centre for Molecular Neurobiology, Griffith University, Nathan,
Qld 4111 Australia. a.mackay-sim@sct.gu.edu.au
Epidemiological evidence and our rat experiments indicate
that low prenatal vitamin D is a biologically plausible risk factor
for schizophrenia. Here, gene arrays are used to provide insights
into how low prenatal vitamin D acts on brain development.
Rat pups born to vitamin D-depleted mothers were depleted until
birth, weaning or adulthood. Control rats had normal vitamin D intake.
At 10 weeks, mRNA was extracted from brains (n= 10/group), pooled
and analysed using rat genome U34A arrays (8800 genes; Affymetrix).
Gene expression was markedly dysregulated in developmentally depleted
animals with 4-40 fold changes over controls of mRNA transcripts
for proteins involved in neurotransmission (2 neurotransmitter transporters);
synaptic function (12 synaptic proteins); cytoskeleton maintenance
(4 proteins); cell cycle control (3 proteins); and signal transduction
(4 signalling proteins). Paradoxically, different genes were affected
in animals depleted until adulthood, with substantial dysregulation
(7-227 fold changes) for mRNA transcripts for prolactin, growth
hormone and other lactogen-related proteins.
These results show that early life vitamin D depletion can induce
long-term effects on brain gene expression. Some of the transcripts
identified in this study were also identified in gene array studies
of post-mortem brain tissue from individuals with schizophrenia.
The results provide clues to cellular pathways by which low vitamin
D could alter brain development in schizophrenia.
Supported by the Stanley Foundation.
Mackay-Sim A, Feron F, Eyles D, Brown J, McGrath (2002).
Low vitamin D disrupts prepulse inhibition in adult but not young
rats: a new animal model of schizophrenia. Schizophrenia Research
53, 216.
LOW VITAMIN D DISRUPTS PRE-PULSE
INHIBITION IN ADULT BUT NOT YOUNG RAT: A NEW ANIMAL MODEL OF SCHIZOPHRENIA.
A Mackay-Sim , J Brown, F Feron, D Eyles, J McGrath
Centre for Molecular Neurobiology, Griffith University, Nathan,
Qld 4111 Australia. a.mackay-sim@sct.gu.edu.au
Epidemiological evidence indicates that prenatal vitamin
D depletion is a non-genetic risk factor for schizophrenia. Here
we test the effect of developmental vitamin D depletion on sensorimotor
gating in rat measured by pre-pulse inhibition of acoustic startle.
Sensorimotor gating is impaired in schizophrenia.
Rat pups born to vitamin D-depleted mothers were depleted until
birth, weaning or adulthood. Control rats had normal vitamin D intake.
Animals were tested for acoustic startle behaviour and open-field
locomotion at 5 weeks and 10 weeks of age. Acoustic startle was
measured with an SR-Lab system using a 65 dB background noise and
startle trials with sound pulses (30mS) of increasing intensity.
Pre-pulse trials included a sound pulse of 70dB or 80dB (50mS) before
a test sound of 120dB. Open-field locomotion was measured by placing
the animal in a circular container and videotaping its movement.
Movement was quantified digitally and distance moved each second
calculated.
The results show that vitamin D depletion alters sensorimotor gating
in a developmentally regulated manner. Pre-pulse inhibition was
disrupted at 10 weeks of age but not at 5 weeks and only in animals
depleted of vitamin D until adulthood. Vitamin D depletion had no
effect on open-field locomotion, on startle threshold or startle
habituation and its effects were similar in males and females.
Developmental vitamin D depletion may be a relevant animal model
for schizophrenia.
Supported by the Stanley Foundation.
Schizophrenia
Let the sun shine in
Feb 7th 2002 | SYDNEY
From The Economist print edition
One cause of schizophrenia may be vitamin-deficient
mothers
SCHIZOPHRENIA is mysterious. In Europe and North America it is commonest
in those born in mid-March. It is more prevalent among people born
in cities than those born in the countryside. And the offspring
of dark-skinned immigrants to northern countries are three to four
times more likely than their pale-skinned confrères to suffer
from it.
That looks like a disparate collection of facts. But John McGrath,
a psychiatrist at the Queensland Centre for Schizophrenia Research
in Wacol, Australia, perceives a connection: vitamin D deficiency.
At a recent meeting of the International Society for Developmental
Neuroscience in Sydney, Dr McGrath and Alan Mackay-Sim, of Griffith
University, Brisbane, presented strong evidence for this theory.
They fed pregnant rats a diet low in vitamin D and studied the offspring.
The results suggest that if a pregnant female rat (and, by extension,
possibly a pregnant female human) is deprived of vitamin D, her
children are at significant risk of schizophrenia.
The connection between the facts in the first paragraph is that
sunlight is an important source of vitamin D. The action of ultra-violet
light from the sun on a molecule called 7-dehydrocholesterol, found
in the skin, turns it into the vitamin. Winter, city life (with
the concomitant shadows cast by tall buildings) and dark skin in
dark climates all reduce this action. The connection with schizophrenia
is that recent work has found receptors for vitamin D in areas of
the developing brain-including regions affected in the disease.
The vitamin also appears to trigger the production of a protein
called nerve growth factor, which directs the development of nerve
cells and promotes their long-term survival.
You cannot, of course, put a rat on a couch and ask it about its
hallucinations. Instead, researchers use a test called pre-pulse
inhibition, or PPI. When a healthy individual, whether rat or human,
is exposed to a quiet pulse of sound before a loud pulse, its tendency
to be startled by the louder one is reduced. Human schizophrenics,
and rats bred to act as "models" of schizophrenia, do
not show this reduced tendency to be startled. Neither did the offspring
of vitamin-D-deprived rats. Dr McGrath and Dr Mackay-Sim also found
enlargement of the brain's ventricles (fluid-filled cavities) in
these rats, as well as thinning of the cortex. Both of these anatomical
changes are seen in human schizophrenics too.
The rats' genes were also affected. The use of gene microarrays,
which measure the activity of lots of genes in a single piece of
tissue, showed that genes known to regulate communication between
nerve cells, and cell survival, were behaving abnormally. Some of
the same genes are known to be disrupted in human schizophrenics.
The upshot is that vitamin D deprivation looks likely to prove a
significant factor in schizophrenia. It is certainly not the whole
cause. In many, if not all, cases, a genetic predisposition also
seems to be involved. And there is evidence that other triggers,
such as maternal viral infections, may play a role. But, unlike
these, vitamin D deficiency is easily dealt with. As Dr McGrath
observes, if standing in the sunshine for a few minutes a day could
be shown to offer some protection to a developing fetus, it is surely
worth a try.
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