Rhesus-associated glycoprotein (RhAG) phenotype of the red blood cells modulates T. gondii infection-associated psychomotor performance reaction times and changes in the human personality profile. Impaired function of the CO2, AQP1, and AQP4 gas channels may cause hypoxia and thus enhance neuroinflammation in autistic individuals

Abstract

It was reported that in humans the response of the host to latent chronic T. gondii infection was dependent on RhD phenotype. Rh-positive individuals, and RhD-positive heterozygotes in particular, appeared to be protected against latent toxoplasmosis-induced changes of personality, increased frequency of traffic accidents, and weight gain disturbances. One may suggest that these disturbances could be associated with development of brain hypoxia because recent studies showed that the Rhesus-associated glycoprotein (CcEe and D proteins) (RhAG) and water channel aquaporin1 (AQP1) were equally responsible for the normal CO2 permeability of the red blood cell membrane. In addition, AQP4, the predominant water channel expressed primarily in astrocytes and ependymocytes in the brain, also regulated hypoxia through mediation of bicarbonate transport, and a hypoxia inducible factor binding motif has been identified in the promoter region of AQP4 gene. It seems that lack or deficiency of RhAG proteins in the host red blood cell membrane and an impaired function of AQP1 and AQP4 water/gas channels in the central nervous system could be associated with various degrees of brain hypoxia. The proinflammatory changes in brain tissue associated with hypoxia may therefore overlap chronic neuroinflammation characteristic for patients with ASD and some other neurodevelopmental disorders, thus affecting the severity of clinical course and intensity of signs and symptoms present in these individuals. The amelioration of several underlying pathophysiological problems in autistic individuals and improvements in clinical symptoms through the use of hyperbaric oxygen therapy is consistent with this reasoning. It is also suggested that an impaired water movement in brain tissues associated with a decreased water channel AQP4 expression in astrocytes and ependymal cells found in autistic patients may be, at least in part, responsible for development of macrocephaly and increased brain weight reported in some of those individuals.

Full text

Chapter
RHESUS-ASSOCIATED GLYCOPROTEIN
(RHAG) PHENOTYPE OF THE RED BLOOD
CELLS MODULATES T. GONDII INFECTION-
ASSOCIATED PSYCHOMOTOR
PERFORMANCE REACTION TIMES AND
CHANGES IN THE HUMAN PERSONALITY
PROFILE. IMPAIRED FUNCTION OF THE
CO2, AQP1, AND AQP4 GAS CHANNELS
MAY CAUSE HYPOXIA AND THUS
ENHANCE NEUROINFLAMMATION IN
AUTISTIC INDIVIDUALS
Joseph Prandota*
* Correspondin Author:
Dr Joseph Prandota,
Department of Social Pediatrics,
Faculty of Health Science, University Medical School,
5 Bartla Street, 51-618, Wroclaw, Poland.
Tel.: +48 71 348 42 10, Fax: +48 71 345 93 24
E-mail: prandota@ak.am.wroc.pl

Joseph Prandota
Dpt of Social Pediatrics, Faculty of Health Sciences, University School of
Medicine, Wroclaw, Poland
ABSTRACT
It was reported that in humans the response of the host to latent
chronic T. gondii infection was dependent on RhD phenotype. Rh-
positive individuals, and RhD-positive heterozygotes in particular,
appeared to be protected against latent toxoplasmosis-induced changes
of personality, increased frequency of traffic accidents, and weight gain
disturbances. One may suggest that these disturbances could be
associated with development of brain hypoxia because recent studies
showed that the Rhesus-associated glycoprotein (CcEe and D proteins)
(RhAG) and water channel aquaporin-1 (AQP1) were equally
responsible for the normal CO2 permeability of the red blood cell
membrane. In addition, AQP4, the predominant water channel
expressed primarily in astrocytes and ependymocytes in the brain, also
regulated hypoxia through mediation of bicarbonate transport, and a
hypoxia inducible factor binding motif has been identified in the
promoter region of AQP4 gene. It seems that lack or deficiency of
RhAG proteins in the host red blood cell membrane and an impaired
function of AQP1 and AQP4 water/gas channels in the central nervous
system could be associated with various degrees of brain hypoxia. The
proinflammatory changes in brain tissue associated with hypoxia may
therefore overlap chronic neuroinflammation characteristic for patients
with ASD and some other neurodevelopmental disorders, thus affecting
the severity of clinical course and intensity of signs and symptoms
present in these individuals. The amelioration of several underlying
pathophysiological problems in autistic individuals and improvements
in clinical symptoms through the use of hyperbaric oxygen therapy is
consistent with this reasoning. It is also suggested that an impaired
water movement in brain tissues associated with a decreased water
channel AQP4 expression in astrocytes and ependymal cells found in
autistic patients may be, at least in part, responsible for development of
macrocephaly and increased brain weight reported in some of those
individuals.
Keywords: T. gondii infection, RhAG phenotype, changes of personality
profile, red blood cell membrane CO2 permeability, aquaporin-1, brain
aquaporin-4, hypoxia, neuroinflammation, autism spectrum disorders, latent
cerebral toxoplasmosis.
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Brain hypoxia May be Due to Defects in RhAG Phenotype and AQP4
EFFECT OF RH PHENOTYPE ON PERSONALITY PROFILE
IN HUMANS WITH LATENT CHRONIC
T. GONDII INFECTION
Approximately 15-85% of the adult human population is chronically
infected by T. gondii depending on geographical areas, hygenic standards,
eating habits, and exposure to cats [1-3], with the brain preferential
involvement [4]. Until recently, it was believed that in the majority of the
cases, human toxoplasmosis has a benign and asymptomatic course but lead
to lifelong persistence of the parasite [5, 6]. In the USA, 1.5 million
infections are estimated to occur annually, with 15% of them being
asymptomatic [7-9]. Infection with T. gondii results in retinochoroiditis in
6% to 20% of immunocompetent individuals [10], and may be responsible
for neurologic and psychiatric symptoms associated with several diseases
[11].
It was reported that young men diagnosed with chronic T. gondii
infection became more introspective, more jealous, easily bored, showed
reduced psychomotor activity and reaction times, were emotionally unstable,
suspicious, had short temper, low self-esteem, and disregarded social rules
[12]. In addition, they were more prone to guilt and showed group
dependency when compared with young women infected with the parasite,
who showed greater self-esteem, were more inteligent, aware, cordial,
participative, amicable, attentive to others, rigid, loyal and self-sufficient,
respected social rules, were sentimental, socially precise, and affective [7, 13,
14]. Both, infected men and women were significantly more anxious than
noninfected individuals [6].
Recently, few independent studies in humans suggested that the response
of the host to latent T. gondii infection was dependent on RhD phenotype
[15-19]. It was demonstrated that RhD-positive individuals, and RhD-
positive heterozygotes in particular, have been protected against latent
toxoplasmosis-induced impairment of psychomotor performance reaction
times estimated by Cattell’s 16PF and Cloninger’s TCI questionnaires as
compared with Rh-negative individuals [15, 18]. Rh-positive heterozygotes
were permanently while Rh-positive heterozygotes were temporarily
protected against such impairment. RhD-positive and RhD-negative
phenotypes had opposite effects on ego strength, praxemia, ergic tension, and
cooperativeness [17]. RhD-positive individuals were also protected against
the parasite-induced increased risk of traffic accidents [16]. A cohort study
3

Joseph Prandota
performed on a population of military conscripts showed that RhD-negative
Toxoplasma-infected individuals had about three times higher probability of
a traffic accident than RhD-negative the parasite-free persons or RhD-
positive (T. gondii-free or Toxoplasma-infected) individuals [16]. In another
study performed on 980 pregnant women it was found that the RhD-
positivity protected T. gondii-infected women against excessive weight gain
in the first trimester of pregnancy [19].
2. DIMINISHED BASAL CO2 PERMEABILITY OF THE
RED BLOOD CELL MEMBRANE. IMPORTANT ROLE OF
THE RHESUS-ASSOCIATED GLYCOPROTEIN (RHAG) AS
A CO2 AND NH3 GAS CHANNELS
The Rh blood group substance is one of the most abundant proteins in
the erythrocyte membrane and the abnormalities of structure in Rhnull red cells
indicate that the Rh family polypeptide proteins plays a role in maintaining
the flattened (biconcave discoid) shape of the erythrocyte [20-23]. This
cytoskeletal function increases the surface area to volume ratio relative to a
sphere and hence the rate of diffusion of gases, including that of CO2 [23].
Callebaut et al. [24] speculated that either Rh (CcEe or D) protein might be a
candidate for a CO2 channel, but Beckmann et al. [25] proposed that both
RhCcEe and RhD proteins, which constitues a heterooligomer with RhAG,
give rise to the immunological differences between Rh-positive and Rh-
negative people [23, 26, 27] may be particularly important to the human
erythrocyte cytoskeleton role of the Rh blood group substance. Recently,
Endeward et al. [28, 29] confirmed that the high CO2 permeability of the
human red blood cell (RBC) membrane was due to the two blood group
membrane proteins (including CcEe and D proteins) and water channel
aquaporin-1 protein (AQP-1), and each of the RhAG and AQP-1 proteins
was responsible for about half of the normal CO 2 permeability of the RBC
membrane [28, 30] (Table 1).
4

Brain hypoxia May be Due to Defects in RhAG Phenotype and AQP4
Table 1. Time required by red blood cells to complete CO2 release
during passage through the lung capillary by 95% (t95%)
Bioparameter PCO2 (cm/sec) T95% (ms)
No membrane
resistance
50
Normal membrane
permeability 0.15 110
AQP-1null or Rhnull
RBCs
0.07 180
Basal permeability
(AQP-1null + DIDS) 0.01 1000
Values calculated for different CO2 permeabilities of the cell membrane.
Intraerythrocytic carbonic anhydrase acitivity was assumed to be nonlimiting.
DIDS, 4,4’-diisothiocyanato-stilbene-2,2’-disulfonate was used as an inhibitor of
RBC permeability. RBCs, red blood cells.
Endeward et al. [29]; with own modification.
3. RELATIVE CO2 AND NH 3 SELECTIVITIES OF AQP1,
AQP4, AND AQP5
Uehlein et al. [31] showed that an AQP plays a physiological role by
enhancing CO2 uptake by plants. Molecular dynamics simulations suggested
that CO2 can pass through the 4 aquapores of an AQP1 tetramer, and
especially through the central pore between the 4 monomers [32]. AQP1 was
reported to be permeable to CO2 [28], O2 [33], and NO [34]. It was suggested
that the hydrophilic NH3 probably moves exclusively through the monomeric
aquapores of AQP1 and RhAG, and less hydrophilic CO2 could move through
the hydrophilic central pores of all 5 channels, including AQP4 [35]. The low
NH3 permeability of AQP4 could protect the brain from rising blood levels of
NH3, while still allowing CO2 and perhaps NO and O2, to pass [35]. It must
be noted that AQP1 constituted an independent channel for CO2 because it
conducted CO2 in the absence of other proteins of the RBC membrane and
had almost no association with the Rh membrane complex [36, 37]. In
addition, RhAG conducted ammonia, and NH3 competing with CO2 for
entrance and passage of the same gas channel may thus impede access of CO2
because the affinity of the channel is somewhat greater for NH 3 than for CO2
[29] (Table 2). Thus, lack or deficiency of one or two of these proteins in the
5

Joseph Prandota
host RBC membrane may be associated with various degrees of hypoxia,
which can play, at least in part, an important role in development of the
abovementioned changes in personality profile, traffic accidents frequency,
and weight gain disturbances associated with latent T. gondii infection.
Amelioration of several underlying pathophysiological problems in the
patients with ASD and improvements in autistic symptoms through the use of
hyperbaric oxygen therapy [38] is in line with this reasoning.
Table 2. PCO2 of human red blood cells with various blood
group deficiencies
Bioparameters PCO2 ± SD
[cm/s]
n [N] PCO2 ± SD
(10 µm DIDS)
[cm/s]
n [N]
Control 0.15 ± 0.08 85 [10] 0.05b ± 0.015 34 [9]
Fynull 0.16 ± 0.08 17 [2] 0.05b ± 0.02 11 [3]
JKnull 0.17 ± 0.09 11 [2] 0.05b ± 0.03 10 [2]
McLeod 0.17 ± 0.10 10 [1] 0.06 b ± 0.03 6 [1]
Kellnull 0.16 ± 0.04 4 [1] 0.07 b ± 0.02 3 [1]
Rh positive 0.17 ± 0.11 13 [4]
Rh negative 0.16 ± 0.07 20 [5]
Rhnull 0.066a ±
0.022
31 [4] 0.029 b ±
0.004
10 [3]
AQP-1null 0.065a ±
0.029
37 [2] 0.015 b ±
0.003
12 [2]
The only blood group deficiencies exhibiting a reduced P CO2 are Rhnull and AQP-1null
(last two lines). aIn the case of Rhnull and AQP-1null, values in the absence of 4,4’-
diisothiocyanato-stilbene-2,2’-disulfonate (DIDS) indicate a significant
difference to the normal control PCO2 (P < 0.02). bSignificant difference between
a PCO2 value in the presence of DIDS and the corresponding value in the absence
of DIDS (P < 0.02). n is a number of single determinations, and numbers in
square brackets, N, are the numbers of blood samples from different persons
studied. The finding of identical PCO2 in Rh-negative and positive red blood cells
argues against the suggestion of Callebout et al. [24] that either Rh protein (D or
CcEe) might be a candidate for a CO2 channel.
Endeward et al. [29]; with own modification.
6

Brain hypoxia May be Due to Defects in RhAG Phenotype and AQP4
4. IMPORTANT ROLE OF AQP-4 IN MEDIATION OF
BICARBONATE TRANSPORT IN THE CENTRAL NERVOUS
SYSTEM AND REGULATION OF HYPOXIA
Immunological analyses have shown that AQP4 occurs primarily in brain
astrocytes [39, 40], and in endothelial cells [41], ependymocytes [42], and
retinal Müller cells, although at lower levels than in astrocytes [43]. AQP4, a
transmembrane water channel protein [44] is strongly expressed especially at
sites of fluid transport including the pial and ependymal surfaces in contact
with cerebrospinal fluid, in the subarachnoidal space, and the ventricular
system [45] suggesting a role in movement of water between brain and
cerebrospinal fluid compartments [46-48].
Neuroanatomical studies revealed extensive structural brain
abnormalities in individuals with autism. Fatemi et al. [49] found that
patients with autism had significantly decreased AQP4 expression in the
cerebellum. Moreover, antibody to AQP4 was identified as its target antigen
in neuromyelitis optica, and serum AQP4 levels in these patients correlated
with clinical disease activity, therefore suggesting that they are involved in
the pathogenesis of the disease [50, 51]. Decreased AQP4 expression may
suggest that cell structure, cell volume and ionic homeostasis are
compromised, especially that Nicchia et al. [52] showed that cultured
astrocytes from AQP4 knockdown mice had altered morphology and reduced
osmotic permeability. AQP4 in astrocytes was also implicated in etiology of
seizures and epilepsy, since it plays a role for K+ clearance [53]. AQP4 null
mice demonstrated an increased seizure threshold, but also increased seizure
duration [54, 55]. In addition, AQP4 astrocytic processes in brain and spinal
cord surround blood vessels, neuronal perikarya and processes thus providing
covering of the brain microvessels [56, 57]. A role in water homeostasis
control has been proposed also for the extracellular matrix, which in brain
consists mainly of chondroitin sulfate proteoglycans. In spinal white matter
the overlap between AQP4, and glial fibrillary acidic proteins (GFAP) is
almost complete [56]. All these suggestions are consistent with the
abovementioned reasoning that T. gondii infection affects several cells and
regions in the brain, including astrocytes, epithelial cells, and subependyma,
and may play an important role in development of cryptogenic epilepsy [5,
11, 58]. In this context, it is therefore not surprising that several authors
found elevated serum antibodies and autoantibodies to brain proteins, such as
for example GFAP [59], brain epithelial cells and nuclei [60, 61], chondroitin
7

Joseph Prandota
sulfate [62], and maternal anti-fetal brain antibodies. The generation of all
these antibodies may reflect a defense reaction of the host to the complexes
consisting of the immunodominant epitopes of T. gondii secreted/excreted
protein antigens and the host antigen proteins present in various brain cells
and structures. This suggestion may be supported by the finding of the host
cell filaments interaction with cysts, for example, an astrocyte can contain
large numbers of parasites [63], and in vitro studies staining for the astrocyte-
specific structural protein GFAP showed that GFAP filaments actively form
around the early cyst wall development phase eventually encasing the cyst in
a tight sheath, possibly to stabilize its formation [64, 65]. This eventual
complex of the parasite antigen proteins/host GFAP filament proteins may be
a target for the elevated serum antibodies and autoantibodies directed against
neuronal and glial filament proteins in autistic individuals found by Singh et
al. [59], and also may serve as an explanation for the elevated GFAP levels in
various brain regions of autistic patients [66, 67].
Decreased AQP4 expression in astrocytes and ependymal cells found in
ASD individuals may be associated, at least in part, with development of
various degrees of brain hypoxia because Nagelhus et al. [43] reported that
this aquaporin mediates water flux, bicarbonate transport, and activity-
dependent volume changes in the brain [43]. In addition, Gunnarson et al.
[68] identified a HIF binding motif in the promoter region of AQP4 gene. In
astrocyte cultures, hypoxia was shown to down-regulate mRNA and protein
content for AQP4 and AQP9 [69]. In rats exposed to focal cerebral ischemia
and in human brain with cerebral infarction AQP4 immunoreactivity was
found be increased [68, 70, 71]. On the other hand, in an animal model for
autism, Fatemi et al. [72] found that prenatal human influenza viral infection
in mice resulted in a downregulation in AQP4 mRNA expression in
neocortex in the offspring at birth and persisted at adolescence [73]. One
cannot therefore exclude that T. gondii infection of the central nervous
system may exert a similar effect.
Finally, because AQP4 is the most abundant water channel in the central
nervous system, decreased AQP4 expression in the brain must be associated
with the impaired water movements between various compartments. This
may, at least in part, be responsible for the brain enlargement characteristic
for autistic patients, especially cerebral and cerebellar gray and white
matters, by approximately 5-10% [74]. In addition, it seems that T. gondii
invasion of various brain cells and structures may contribute to the generation
of the antibodies against AQP4 found in patients with neuromyelitis optica
[50, 51]. Relapses of this clinical entity preceded by a rise in serum AQP4
8

Brain hypoxia May be Due to Defects in RhAG Phenotype and AQP4
antibody levels strenghtens the case for the parasite possible involvement in
the pathogenesis of this disease.
Recently Rajnarayanan et al. [75] reported that also AQP11 is expressed
in Purkinje cells in the cerebellum, which are known target cells in ASD
individuals. It was found that AQP11 is the only mammalian aquaporin that
has tri-cysteine motif, a high affinity mercury ion binding site [75]. This
property of AQP11 may, at least in part, explain why thimerosal, an
ethylmercury-containing preservative in some vaccines, has a high affinity to
the brain and therefore may accumulate in this tissue, thus possibly
contributing to the risk of autism and other neurodevelopmental disorders
[76]. This reasoning may be supported by the finding that single-dose
exposure to methylmercury in mice with chronic T. gondii infection showed
a synergistic effect, with effects of methylmercury especially on the immune
system and an increase in brain tissue cyst counts [77]. Thus, one cannot
exclude that latent congenital T. gondii infection of the central nervous
system may be a triggering factor responsible for development of ASD and
other neurologic abnormalities in humans.
5. HYPOXIA MAY TRIGGER REACTIVATION OF LATENT
CEREBRAL TOXOPLASMOSIS BECAUSE IT ACTIVATES
HYPOXIA INDUCING FACTOR-1 ASSOCIATED WITH A
PROINFLAMMATORY ACTIVITY
Cerebral toxoplasmosis has special predilection to the caudate nucleus,
subependyma, periaqueductal area, and include perivascular vasculitis [5]. In
humans, neurons, astrocytes, vascular endothelia, and pericytes have been
implicated in the intracellular proliferation of T. gondii in vivo and in vitro
[78-80]. Lüder et al. [58] found that two days post infection with T. gondii
tachyzoites, intracellular parasites were detected within neurons, astrocytes,
and microglial cells of Wistar rat embryos, and 30% of the microglial cells
harbored intracellular parasites. Tachyzoites have been identified in choroid
plexuses causing cerebral toxoplasmosis in AIDS patients [47, 81], and
invaded Purkinje cells in the cerebellum [7], which may indicate that
selective vulnerability of these cells (loss and atrophy) plays an important
role in the etiopathogenesis of autism [66, 82, 83]. Recent reports suggested
that in adults, chronic T. gondii infection with brain cysts could be the cause
of development of headache and cryptogenic epilepsy [84, 85], high
9

Joseph Prandota
frequency of epilepsy in some groups of autistic patients [86], autism
spectrum disorders, obsessive-compulsive disorder [87], and other
neurodevelopmental abnormalities [11, 88-90].
Individuals with RhAGnull red cells phenotype and an impaired function
of AQP-1 and AQP-4 gas channels may experience various degrees of brain
hypoxia. It must be emphasized that T. gondii activates hypoxia-inducible
factor 1 (HIF1) already at physiologically relevant oxygen levels and requires
HIF1 for growth and survival [91]. Hypoxia is associated with an increase in
generation of various pro- and antiinflammatory cytokines and other
biomediators, such as TNF-α, IL-1-β, IL-6, IL-8, chemokines (monocyte
chemoattractant protein-1, CC-chemokine receptor 2, macrophage
inflammatory protein-1α, intercellular adhesion molecule-1), acute phase
proteins gene expression, COX-2 gene transcription, and heme oxygenase-1
(HO-1) [92-101], induction of iNOS [102], and reactive oxygen species
[103]. Moreover, hypoxia markedly decreased T-lymphocyte IL-2 mRNA, a
key cytokine responsible for B-cell proliferation and immunoglobulin
secretion, and ischemic tissues demonstrated intravascular neutrophil
accumulation, vascular damage, and increased vascular wall permeability
[94]. Exposure of primary rat microglial cultures, as well as established
microglial cell line BV-2 to hypoxia induced expression of iNOS and NO
production, indicating that hypoxia could lead also to the inflammatory
activation of microglia involving activation of HIF-1α [104]. HIF-1α is the
master regulator of oxygen homeostasis to meet cell and tissue requirements
in a situation of oxygen deficiency, and NO impairs normoxic degradation of
this biomolecule by inhibition of prolyl hydroxylases [105]. In addition, NO
induces the synthesis of vascular endothelial growth factor by rat vascular
smooth muscle cells, which brings about proliferation of endothelial cells and
increases permeability of the vessel wall [106]. Some biomarkers gene
expression induced by HIF-α are presented in Table 3.
On the other hand, astrocytes induce heme oxygenase-1 (HO-1
expression in microglia, which has protective antioxidant, antiapoptotic, and
anti-inflammatory functions [95], thus providing mechanism for preventing
excessive brain inflammation [100]. Mimickers of HO-1 products, such as
bilirubin, ferrous iron, and a carbon monoxide-releasing molecule reduced
IFN-γ-induced iNOS expression and/or NO release [100]. Transforming
growth factor-β (Table 1) has also been shown to induce HO-1 expression in
microglia [100], and in epithelial cells [107]. The important role of hypoxia
in the pathogenesis of several diseases may be supported by the reports that
10

Brain hypoxia May be Due to Defects in RhAG Phenotype and AQP4
arterial blood oxygen desaturation played a key role in development of SIDS,
refractory hypoxemia was present in patients with pulmonary right-to-left
shunts, subjects with obstructive sleep-apnea syndrome, decompression
illness, and in patients with migraine associated with patent foramen ovale
and atrial septal defects [108-114]. The inflammatory changes in the brain
associated with hypoxia may thus overlap with chronic neuroinflammation
characteristic for ASD individuals [115, 116], thus enhancing severity of the
clinical course, signs and symptoms of ASD.
Table 3. Hypoxia inducible gene expressiona [113]
Erythropoietin
IL-1, IL-6, IL-8
Nitric oxide synthase-2
Heme oxygenase-1
Ornithine decarboxylase; hexokinase 2
Phosphofructokinase L; phosphoglycerate kinase-1
Pyruvate kinase M; glucose transporter-1, -3
Lactate dehydrogenase A
Glyceraldehyde-3-phosphate dehydrogenase
Insulin-like growth factor-2; enolase 1
Aldolase A, C; adenylate kinase 3
Pituitary adenylate cyclase-activating polypeptide
Transforming growth factor β3
Vascular endothelial growth factor
aT. gondii activates hypoxia-inducible factor 1 (HIF1) already at physiologically
relevant oxygen levels and requires HIF1 for growth and survival [91].
6. THE MACROCEPHALY AND INCREASED BRAIN SIZE
CHARACTERISTIC FOR SOME AUTISTIC INDIVIDUALS
MAY BE CAUSED BY A DECREASED AQP4 EXPRESSION
IN THE CENTRAL NERVOUS SYSTEM
Water movement in brain tissues is carefully regulated with
aquaporinAQP1 and AQP4 are the major water channels expressed at fluid-
tissue barriers throughout the brain and play a crucial role in cerebral water
balance. AQP1 is densely packed in choroid plexus cells lining the ventricles
11

Joseph Prandota
and was found to be responsible for cerebrospinal fluid production. AQP4 is
abundant in astrocytes and concentrated in the end-feet structures that
surround capillaries throughout the brain and are present in glia limiting
structures, notably in osmosensory areas, such as the supraoptic nucleus
[117]. It seems therefore that disturbances in these aquaporins function in the
brain may have serious pathophysiological consequences, including a
suggestion that AQP4 may be a target for therapy in brain edema [117]. It is
important therefore that recently, in the cerebellum of autistic patients Fatemi
et al. [73] demonstrated a markedly decreased AQP4 expression. On the
other hand, one must emphasize that morphometric and chemical
neuroimaging studies performed during early childhood in such individuals
showed abnormal brain volume enlargement [74]. At birth, the average head
circumference was almost normal [118], but by 3-4 years of age, brain size
increased normal range by about 10% [119], with a persistent about 5%
difference at older ages [120]. One may suggest therefore that these
abnormalities may be, at least in part, responsible for the impaired water
transport in the brain of some autistic individuals due to the AQP4
irregularities. This recommendation may be supported by the finding that
AQP4-deficient mice had a significantly increased brain extracellular space
volume fraction by about 28% [121]. Moreover, studies on ontogeny of water
transport in rat brain revealed very low levels of AQP4 in the first postnatal
week, a pronounced increase was noted in the second week (from 2% of
adult level at postnatal day 7 to 25% at postnatal day 14) [122]. Finally,
Fujita et al. [69] postulated that the restoration in AQP4 and AQP5
expression levels in cultured rat astrocytes at 32oC from hypoxia-induced
decrease at 37oC is one of the mechanisms by which brain edema is improved
by mild hypothermia under hypoxic conditions. Thus, the above-presented
argumentation is consistent with the changes of head circumference and brain
size during early postnatal developmental age reported in autistic children
[74].
In summary, it seems that RhAGnull red cells phenotype and an impaired
function of AQP-1 and AQP-4 gas channels associated with various degrees
of brain hypoxia may be, at least in part, responsible for the changes in the
personality profiles in some individuals with latent chronic T. gondii
infection. These abnormalities may therefore also affect clinical course and
intensity of signs and symptoms in the patients with ASD and/or other
neurologic disorders. The amelioration of several underlying
pathophysiological disturbances in autistic individuals and improvements in
clinical symptoms through the use of hyperbaric oxygen therapy is consistent
12

Brain hypoxia May be Due to Defects in RhAG Phenotype and AQP4
with this argumentation [38]. Finally, one may also suggest that the
macrocephaly and increased brain size characteristic for some autistic
individuals was caused by the significantly decreased AQP4 expression in
the brain.
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