Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals
Korrapati V. Sathyasaikumar1, Erin K. Stachowski1, Ikwunga Wonodi1, Rosalinda C. Roberts1,2, Arash Rassoulpour1,
Robert P. McMahon1, and Robert Schwarcz*,1
1Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore;2Present
address: Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, AL 35294
7635, fax: 410-747-2434, e-mail: email@example.com
The levels of kynurenic acid (KYNA), an astrocyte-
derived metabolite of the branched kynurenine pathway
(KP) of tryptophan degradation and antagonist of a7 nic-
otinic acetylcholine and N-methyl-D-aspartate receptors,
are elevated in the prefrontal cortex (PFC) of individuals
with schizophrenia (SZ). Because endogenous KYNA
modulates extracellular glutamate and acetylcholine lev-
els in the PFC, these increases may be pathophysiologi-
cally significant. Using brain tissue from SZ patients and
matched controls, we now measured the activity of sev-
[KMO], kynureninase, 3-hydroxyanthranilic acid dioxy-
genase [3-HAO], quinolinic acid phosphoribosyltransfer-
ase [QPRT], and kynurenine aminotransferase II [KAT
II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Com-
pared with controls, the activities of KMO (in BA 9 and
10) and 3-HAO (in BA 9) were significantly reduced in
SZ, though there were no significant differences between
patients and controls in kynureninase, QPRT, and KAT
II. In the same samples, we also confirmed the increase in
the tissue levels of KYNA in SZ. As examined in rats
treated chronically with the antipsychotic drug risperi-
done, the observed biochemical changes were not second-
ary to medication. A persistent reduction in KMO
activity may have a particular bearing on pathology be-
cause it may signify a shift of KP metabolism toward en-
hanced KYNA synthesis. The present results further
support the hypothesis that the normalization of cortical
KP metabolism may constitute an effective new treat-
ment strategy in SZ.
Key words: kynurenine3-monooxygenase (KMO)/
kynurenic acid/a7 nicotinic acetylcholine receptor/
NMDA receptor/prefrontal cortex
Neuroanatomical, neurochemical, genetic, and func-
tional studies have provided a large body of evidence
function in the prefrontal cortex (PFC; see Gur et al1,
Pakkenberg et al2, and Eisenberg and Berman3for recent
reviews). These abnormalities are not only believed to
play a critical role in psychosis but probably also account
for the incapacitating cognitive deficits seen in patients,
including poor memory and executive functions.4–6Most
current thinking regarding the neurochemistry of cogni-
tive impairment in SZ invokes distinct interdependent
changes in major neurotransmitter systems within the
PFC. Thus, while the precise nature and causes of the ab-
normalities are not well understood, and although there
is an increased awareness of additional factors,7–9there is
general consensus that changes in cholinergic and gluta-
matergic function are critically involved in the patho-
physiology of SZ.10,11
Recent studies suggest that kynurenic acid (KYNA),
a metabolite produced in a dead-end side arm of the
kynurenine pathway (KP) of tryptophan degradation
(figure 1), might also be involved in prefrontal dysfunc-
tions in SZ. Present in the mammalian brain in low
(rodents) to high (human) nanomolar concentrations,
KYNA is an antagonist of two receptors that are closely
linked to cognitive phenomena and psychosis, ie, the
a7 nicotinic acetylcholine receptor (a7nAChR)12and the
N-methyl-D-aspartate (NMDA) receptor.13By reducing
the function of one or both of these receptors, increases
in brain KYNA levels might therefore cause hypo-
nicotinergic and hypoglutamatergic conditions. Acute,
KYNA-induced blockade of a7nAChR, in particular,
has been shown to have interesting downstream effects
in the PFC, including decreases in the extracellular levels
Schizophrenia Bulletin vol. 37 no. 6 pp. 1147–1156, 2011
Advance Access publication on October 29, 2010
? The Author 2010. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
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of glutamate.14,15On a functional level, enhanced brain
KYNA has been demonstrated to cause cognitive deficits
in animals.16–19Interestingly, reductions in brain KYNA
levels lead to increases in the extracellular concentrations
KYNA might function as abidirectional modulator of glu-
tamatergic and nicotinergic neurotransmission.14,15,20No-
tably, this reduction in brain KYNA formation causes
significant cognitive improvements, which can be demon-
strated both in behavioral paradigms and using electro-
physiological outcome measures.21Taken together, these
findings underscore the need to understand the dynamics
of the disposition and function of KYNA in the mamma-
We reported previously that KYNA levels in the
PFC are significantly elevated in individuals with SZ.22
The present study constitutes a first effort to explore
the cause(s) of these high KYNA levels. To this end,
we used postmortem tissue samples from SZ patients
and matched control subjects and determined the activ-
ities of several KP enzymes in two topographically de-
fined key regions of the PFC, Brodmann areas (BA) 9
and 10. All enzymes selected, ie, kynurenine aminotrans-
ferase II (KAT II), kynurenine 3-monooxygenase
(KMO), kynureninase, 3-hydroxyanthranilic acid dioxy-
genase (3-HAO), and quinolinic acid phosphoribosyl-
transferase (QPRT), act downstream of the pivotal KP
metabolite kynurenine. These enzymes are located in
two physically segregated arms of the pathway, produc-
hydroxykynurenine and 3-hydroxyanthranilic acid, as
well as the excitotoxic NMDA receptor agonist quino-
linic acid, in microglial cells23(figure 1). Possibly signify-
ing a shift toward enhanced KYNA formation, our
in the microglial branch of the KP in the disease.
hydroxykynurenine, and KYNA were purchased from
Sigma Chemical Co. (St Louis, Missouri). All other bio-
chemicals and chemicals were ‘‘reagent grade’’ and were
purchased from a variety of commercial suppliers. Ris-
peridone (Risperdal; Janssen-Ortho) was obtained from
Global Drugs Direct (Vancouver, British Columbia,
Canada). The KMO inhibitor Ro 61-8048 was kindly
provided by Dr W. Fro ¨stl (Novartis, Basel, Switzerland).
Radioactive enzyme substrates were custom synthe-
sized by Amersham Corp. (Arlington Heights, Illinois;
L-5-3H-kynurenine [12 Ci/mmol] and
acid [27 Ci/mmol]) and DuPont/New England Nuclear
Fig. 1. The kynurenine pathway of tryptophan degradation, indicating the enzymes measured in the present study. Large open arrows:
differences between schizophrenia and control tissues, as described in the text.
K. V. Sathyasaikumar et al.
Human Brain Tissue
Specimens were obtained from the Maryland Brain Col-
lection, a repository of postmortem tissue maintained in
cooperation with the Office of the Chief Medical Exam-
Psychiatric Research Center. Normal control subjects
(n = 15) were free ofneurological or psychiatricdisorders.
Patients (n = 15) met Diagnostic and Statistical Manual of
Mental Disorders, Third Edition Revised, criteria for SZ,
ascertained by consensus of two research psychiatrists.
The diagnosis was based on information from clinical
records and family members. The latter were interviewed
by phone, using the Diagnostic Evaluation after Death24
and an informant version of the Structured Clinical
Interview. In cases where death was witnessed, the
time between death and autopsy was taken as the post-
mortem interval (PMI). Otherwise, the PMI was defined
as the time halfway between the brain donor being found
dead and being last seen alive. Only cases with a PMI of
less than 24 hours were used for this study.
Two regions of the cerebral cortex (BA 9 and BA 10)
were dissected out, and the tissue was stored at ?80?C
prior to analysis. Brain samples were weighed while fro-
zen and then homogenized (1:5, wt/vol) by sonication
(Branson Ultrasonics Corp., Danbury, Connecticut) in
ultrapure water. The tissue homogenate was then divided
into aliquots for the determination of KYNA levels and
KP enzyme activities. For each tissue preparation, all
enzyme assays were performed on the same day.
effects of chronic risperidone treatment. The animals were
group-housed in a temperature-controlled Association for
Assessment and Accreditation of Laboratory Animal
Care-approved animal facility at the University of Mary-
land School of Medicine and were kept on a 12/12-hour
light/dark cycle with free access to food and water.
Animals received daily intraperitoneal (i.p.) injections
of risperidone (3 mg/kg body weight25) at 4 PM. Vehicle-
treated rats served as controls. After 28 days, rats were
deeply anesthetized with chloral hydrate (360 mg/kg,
sected out, frozen on dry ice, and stored at ?80?C. After
thawing, the tissue was processed for KYNA and enzyme
analyses, as described below for human brain tissue.
The original tissue homogenate was further diluted (1:1,
vol/vol) with ultrapure water. Perchloric acid (6%; 50 ll
for human and 25 ll for rat) was then added to 100 ll of
the tissue preparation, and the precipitated proteins were
removed by centrifugation (16000g, 15 min). Twenty
microliters of the resulting supernatant were subjected
to high-performance liquid chromatography (HPLC)
analysis. KYNA was isocratically eluted from a 3-lm
C18 reverse-phase column (80 mm 3 4.6 mm; ESA,
Chelmsford, Massachusetts), using a mobile phase
containing 250mM zinc acetate, 50mM sodium acetate,
and 5% acetonitrile (pH adjusted to 6.2 with glacial
acetic acid), using a flow rate of 1.0 ml/minute. In the
eluate, KYNA was quantitated fluorimetrically (excita-
tion: 344 nm, emission: 398 nm; Perkin Elmer Series
200 fluorescence detector [Perkin Elmer, Waltham,
Massachusetts]). The retention time of KYNA was
approximately 7 minutes.
1:10 (vol/vol) in 100mM Tris-HCl buffer (pH 8.1) con-
taining 10mM KCl and 1mM EDTA, 100 ll of the tissue
preparation were incubated for 40 minutes at 37?C in
a solution containing 1 mM NADPH (nicotinamide
adenine dinucleotide phosphate; reduced form), 3mM
glucose-6-phosphate, 1 U/ml glucose-6-phosphate dehy-
drogenase, 100lM kynurenine, 10mM KCl, and 1mM
EDTA in a total volume of 200 ll. For kinetic analyses,
becauseof limited tissue availability, equaltissue aliquots
SZ). The pooled tissues were homogenized (1:25, wt/vol),
and KMO activity was determined in the presence of 1–
100lM kynurenine. The reaction was stopped by the addi-
tion of 50 ll of 6% perchloric acid. Blanks were obtained
either by adding the tissue preparation at the end of the
incubation, ie, prior to the denaturing acid, or by including
the specific enzyme inhibitor Ro 61-804826(100lM) in the
incubation solution. After centrifugation (16000g, 15 min),
20 ll of the supernatant was appliedtoa3-lm HPLC col-
consisting of 1.5% acetonitrile, 0.9% triethylamine, 0.59%
tane sulfonic acid. In the eluate, the reaction product, 3-
hydroxykynurenine, was detected electrochemically using
either a Coulochem 5100A detector27(ESA; oxidation po-
tential: þ0.2 V; flow rate: 1.0 ml/min) or an HTEC 500 de-
tector (Eicom Corp., San Diego, California; oxidation
potential: þ0.5 V; flow rate: 0.5 ml/min). Depending on
ied between 5.5 and 11 minutes.
KMO activity in rat brain was determined in an iden-
tical manner except that 80 ll of a 1:10 (wt/vol) homog-
enate were used in the assay.
After diluting the original homogenate
was further diluted (1:100, vol/vol) with 5mM Tris-HCl
(pH 8.4) containing 10mM of 2-mercaptoethanol and
The original tissue homogenate
Kynurenine Pathway Metabolism in Schizophrenia
50lMpyridoxal-5#-phosphate. Eighty microliters of the
tissue preparation were then incubated for 2 hours at
37?C in a solution containing 90mM Tris-HCl buffer
(pH 8.4) and 4lM DL-3-hydroxykynurenine in a total
volume of 200 ll. The reaction was terminated by add-
ing 50 ll of 6% perchloric acid. To obtain blanks, tissue
homogenate was added at the end of the incubation, ie,
immediately prior to the denaturing acid. After centri-
fugation to remove the precipitate (16 000g, 15 min),
25 ll of the resulting supernatant was applied to a
5-lm C18 reverse-phase HPLC column (Adsorbosil;
150 mm 3 4.6 mm; Grace, Deerfield, Illinois) using
a mobile phase containing 100mM sodium acetate
(pH 5.8) and 1% acetonitrile at a flow rate of 1.0 ml/
minute. In the eluate,thereactionproduct,3-hydroxyan-
emission wavelength of 414 nm. The retention time of
3-hydroxyanthranilic acid was ;4 minutes.
luted (1:4, vol/vol) in 60mM 2-(N-morpholino)ethane
sulfonic acid buffer, pH 6.0, and 100 ll of the tissue prep-
aration were incubated for 1 hour at 37?C in a solution
containing 153lM Fe(NH4)2SO4, 0.01% ascorbic acid,
and 3lM [1-14C]-3-hydroxyanthranilic acid (5 nCi) in
a total volume of 200 ll. Blanks were obtained using
heat-inactivated tissue. The reaction was terminated by
the addition of 50 ll of 6% perchloric acid, and the result-
ing precipitate was removed by centrifugation (16 000g,
15 min). The supernatant, containing newly formed14C-
quinolinic acid, was applied to a Dowex 50W (Hþ-form)
cation exchange column, and radioactivity in the eluate
was quantitated by liquid scintillation spectrometry.28
The same protocol was followed to measure 3-HAO
activity in rat brain, using 100 ll of the original tissue
homogenate (1:10, wt/vol).
The original tissue homogenate was di-
homogenate were incubated for 2 hours at 37?C in
a solution containing 50mM potassium phosphate buffer
(pH 6.5), 10mM 2-mercaptoethanol, 1mM MgCl2,
1mM phosphoribosylpyrophosphate, and 20nM [3H]-
quinolinic acid (30 nCi) in a total volume of 500 ll.
Blanks were obtained using heat-inactivated tissue.
The reaction was terminated by placing the tubes on
ice, and particulate matter was separated by centrifuga-
tion (16000g, 10 min). Newly formed3H-nicotinic acid
mononucleotide was recovered from a Dowex AG 1 3 8
anion exchange column and quantitated by liquid
Forty microliters of the original tissue
KAT II Activity.
further diluted (1:1, vol/vol) in 5mM Tris-acetate buffer,
pH 8.0, containing 10mM 2-mercaptoethanol and 50lM
The original tissue homogenate was
preparation were incubated for 20 hours at 37?C in a re-
action mixture containing 150mM Tris-acetate buffer,
pH 7.4, 2lM kynurenine, 0.79lM
nCi), 1mM pyruvate, and 80lM pyridoxal-5#-phosphate
(total volume: 200 ll).30,31Blanks were obtained using
heat-inactivated tissue. The reaction was terminated by
the addition of 20 ll of 50% (wt/vol) trichloroacetic
acid and 1 ml of 0.1 M HCl, and the precipitated proteins
were removed by centrifugation (16000g, 10 min). Newly
change chromatography (Dowex 50W; Hþ-form) and
quantitated by liquid scintillation spectrometry as
3H-KYNA was then purified by cation ex-
The protein content of tissue samples was determined by
the method of Lowry et al32using bovine serum albumin
as a standard.
Data from controls and SZ patients were compared using
SAS PROC MIXED to fit a mixed model for repeat
measures ANCOVA, using the model: analyte = age þ
brain region (BA 9 or BA 10) þ diagnosis (control or
SZ)þ diagnosis 3 brain region,where the repeatedfactor
was multiple samples from two regions of the same brain.
Post hoc contrasts from this model were used to estimate
age-adjusted differences between groups for each brain
Differences in the distribution of analytes were com-
pared between individuals with SZ who were on and
with P-values calculated by the exact (permutation)
method, as implemented in SAS PROC NPAR1WAY.
Data obtained in control and risperidone-treated rats
were compared using Student t test.
Age, sex, PMI, subtype of SZ, and antipsychotic treat-
ment at the time of death are listed for all brain donors
(table 1). The cases were well matched and showed no
statistically significant group differences in any of the de-
mographic categories. Moreover, there was no apparent
effect of PMI, sex, or drug treatment on any of the bio-
chemical measures described here. Effects of age (<70
years) were similar in both groups and were adjusted
for in ANCOVA models comparing the groups.
Mean KYNA concentrations in control tissue in BA 9
and BA 10 were 1.7 6 0.2 and 2.2 6 0.2 pmol/mg protein,
respectively (mean 6 standard error of the mean [SEM]).
K. V. Sathyasaikumar et al.
As illustrated in figure 2 using individual data points, av-
erage KYNA values in individuals with SZ were elevated
compared with controls (by 46.8% and 83.4%, respec-
tively), with the difference approaching significance in
BA 9 [t(27) = 1.98, P = .058] and attaining significance
in BA 10 [t(28) = 2.73, P = .011].
25.7 6 2.9 and 28.9 6 3.3 pmol/hour/mg protein, respec-
tively (mean 6 SEM). Compared with controls, enzyme
activityin SZpatientswas reducedby36.0%[t(27)=2.62,
P = .014] and 38.3% [t(28) = 2.55, P = .017], respectively,
in these brain areas (figure 3A). Kinetic analyses,
obtained from single tissue preparations using equal ali-
quots from five control and five SZ brain homogenates,
indicated that the reductions in enzyme activity in SZ in
both BA 9 (figure 3B) and BA10 (figure 3C) appeared to
be a reflection of decreased vmax values rather than
ControlKMO activitiesin BA9 andBA 10 were
changes in substrate affinity (BA 9—control: vmax =
2.1 pmol/hour/mg tissue, Km= 37.1lM; SZ: vmax= 1.7
pmol/hour/mg tissue, Km= 49.7lM; BA 10—control:
vmax = 4.6 pmol/hour/mg tissue, Km = 73.6lM; SZ:
vmax= 1.3 pmol/hour/mg tissue, Km= 30.8lM).
were 297.9 6 53.8 and 127.7 6 33.6 pmol/hour/mg pro-
tein, respectively (mean 6 SEM). Compared with con-
trols, decreases in enzyme activity were observed in SZ
patients in both BA 9 and BA 10 (figure 4). This reduc-
tion was statistically significant in BA 9 [t(27) = 2.76, P =
.01] but not in BA 10 [t(27)=0.85, P = .40].
Control 3-HAO activities in BA 9 and BA 10
kynureninase, QPRT, and KAT II in BA 9 and BA 10
were 86.1 6 14.3 and 55.3 6 10.3 pmol/hour/mg protein,
66.8 69.6and63.5 610.0fmol/hour/mgprotein,and0.21
6 0.02 and 0.16 6 0.02 pmol/hour/mg protein, respec-
tively (means 6 SEM). None of these enzyme activities
showed differences between controls and SZ patients
in BA 9 and BA 10 (minimum P > .22; figures 5A–C).
Control activities for
Chronic Risperidone Treatment in Rats
In order to control for possible effects of antipsychotic
medication, the tissue levels of KYNA and the activities
of the two KP enzymes that had shown significant
changes in SZ (KMO and 3-HAO) were determined in
the frontal cortex of rats that had been treated for 28
days with risperidone or vehicle (n = 8 per group). Con-
trol levels of KYNA were 181.3 6 59.5 fmol/mg protein,
and control enzyme activities were 13.2 6 3.7 (KMO) and
198.0 6 15.6 (3-HAO) pmol/hour/mg protein, respec-
tively (mean 6 SEM). Neither KYNA levels [t(14) =
0.33, P = .74] nor KMO [t(14) = 0.81, P = .43] or 3-
HAO [t(14) = 0.14, P = .89] activity differed significantly
Table 1. Demographics of Brain Donors
GroupA/G/R PMI SubDxAntipsychotic
Note: A, age (in y); G, gender; M, male, F, female; R, race; C,
Caucasian; AA, African American; PMI, postmortem interval
(in h); CUT, chronic undifferentiated type; SubDx,
subdiagnosis; SZ, schizophrenia. Age (mean 6 SEM)—controls:
46.7 6 4.2; SZ: 50.0 6 4.4. PMI (mean 6 SEM)—controls:
11.0 6 1.7; SZ: 11.0 6 2.0.
9 and BA 10 in controls (squares) and schizophrenia patients
(triangles). Horizontal lines indicate mean values. *P < .05
(ANCOVA post hoc test).
Kynurenine Pathway Metabolism in Schizophrenia
The present study, which was designed to explore mech-
anisms underlying the increase in brain KYNA levels in
the PFC of individuals with SZ, revealed distinct abnor-
malities in KP enzymes in both cortical regions studied,
ie, BA 9 and BA 10. These changes in SZ, which were not
related to demographics, were restricted to enzymes in
the main branch of the KP, whereas the activity of
range. Moreover, both the patients’ medication history
and complementary studies in chronically risperidone-
treated rats indicated that the results of our study were
not affected by antipsychotic drug use. Our data there-
fore provide insights into the pathophysiology of SZ
and also suggest new treatment strategies.
The tryptophan metabolite kynurenine occupies a
central position in the KP (figure 1). In the brain, kynur-
enine gives rise to two physically segregated branches of
the pathway, producing 3-hydroxykynurenine and its
downstream metabolites 3-hydroxyanthranilic acid and
quinolinic acid in microglial cells and KYNA in astro-
microglial compounds, which are neurotoxins and gener-
ators of highly reactive free radicals, may play significant
roles in brain pathology.33–37Astrocyte-derived KYNA,
in contrast, has neuroprotective properties due to its
ability to block neuronal excitation and scavenge free
Of the enzymes that use kynurenine as a substrate,
KMO is the most specific and has the lowest Km, and
is therefore rate limiting. Reduced KMO activity will de-
crease the flux of the KP toward quinolinic acid and
might therefore indirectly provide a degree of neuropro-
tection. We have previously proposed that this can be
exploited for the treatment of Huntington’s disease
and other neurodegenerative disorders by cautiously tar-
geting KMO with specific enzyme inhibitors.40
The present study revealed a significant decrease in
KMO activity in the PFC of individuals with SZ. This
reduction, which was tentatively linked to a lower vmax
crease in the activity of kynureninase, the next enzyme in
the metabolic cascade. On the contrary, kynureninase ac-
tivity in SZ tended to be higher than in controls, though
the difference did not attain statistical significance in ei-
ther of the two prefrontal regions studied. It therefore
appears that the observed reduction in KMO activity
is not a reflection of a generalized microglial abnormal-
ity, which has been invoked to play a significant role in
SZ and interpreted as an indication of a compromised
immune system in the disease.41–45In light of recent stud-
ies, it is more likely that the impairment of KMO activity
Fig. 4. Individual case representation of 3-hydroxyanthranilic acid
dioxygenase activity in BA 9 and BA 10 in controls (squares) and
schizophrenia patients (triangles). Horizontal lines indicate mean
values. *P < .05 vs controls (ANCOVA post hoc test). ns, not
Fig. 3. (A) Individual case representation of kynurenine 3-
monooxygenase (KMO) activity in BA 9 and BA 10 in controls
(squares) and schizophrenia (SZ) patients (triangles). Horizontal
lines indicate mean values. *P < .05 (ANCOVA post hoc test). (B
and C) Kinetic characteristics of KMO activity in BA 9 and BA 10,
respectively. [S], kynurenine concentration.
K. V. Sathyasaikumar et al.
iants in the KMO gene.46,47
The activity of 3-HAO, which catalyzes the formation
of the NMDA receptor agonist quinolinic acid from 3-
hydroxyanthranilic acid, was found to be reduced in
BA 9, ie, the dorsolateral subdivision of the PFC that
is preferentially involved in sustaining attention and
working memory.48A tendency toward lower 3-HAO ac-
tivity was also observed in BA 10, though the results were
not statistically significant. Decreased 3-HAO activity
might account for the elevation in the tissue levels of
3-hydroxyanthranilic acid in SZ, which was recently
affect the redox status of neurons and glial cells in the
area (see above). In addition, reduced 3-HAO activity
will translate into lower quinolinic acid formation and
may thus possibly contribute to NMDA receptor
No disease-related changes were seen in the activity of
the next enzyme in the cascade, QPRT, in either region of
the PFC. This further supports the notion that distinct,
rather than generalized, KP impairments exist in the
brain of patients with SZ. Studies currently in progress
in our laboratory are designed to elucidate the genetic
underpinnings and molecular mechanisms of the discrete
anomaliesin KP metabolism reported here. In particular,
we are investigating the possible role of cosubstrates,
ie, KMO and 3-HAO, such as molecular oxygen, metal
ions, and the endogenous anti-oxidant glutathione,50,51
all of which are established risk factors in SZ (see Brown
and Susser52and Do et al53for recent reviews).
The question then arises whether and how specific
impairments in KP enzymes might account for the signif-
icant increases in prefrontal KYNA levels in SZ, which
were originally described in 2001.22The most parsimoni-
ousexplanation wouldbe thata reductionin KMOactiv-
ity eventually triggers a shift in cerebral KP metabolism
Fig. 5. Individual case representation of kynureninase (A),
quinolinic acid phosphoribosyltransferase (B), and kynurenine
aminotransferase II (C) activity in BA 9 and BA 10 in controls
(squares) and schizophrenia (SZ) patients (triangles). Horizontal
between controls and SZ patients (all P > .05; ANCOVA post hoc
tests). ns, not significant.
intraperitoneally) does not alter the tissue levels of kynurenic
acid and the activities of kynurenine 3-monooxygenase and
3-hydroxyanthranilic acid dioxygenase in the rat frontal cortex (all
P > .1; student t test). Data are mean 6 standard error of the mean
(SEM) (n 5 eight animals per group).
Kynurenine Pathway Metabolism in Schizophrenia
toward enhanced KYNA formation in SZ. As demon-
strated in a recent in vivo study in rats, such a redirection
of KP metabolism toward increased KYNA synthesis
does not occur in the normal brain when KMO activity
tions when the experiment is performed in injured brain
tissue where glial functions are abnormal.54This mecha-
nism may therefore also operate in SZ, where microglial
described (see above).42,55–57Moreover, it is quite con-
ceivable that prolonged downregulation of KMO, as
opposed to the effects of acute enzyme inhibition studied
by Amori et al,54will eventually favor KYNA synthesis
over the synthesis of 3-hydroxykynurenine.
The dynamics of the pivotal metabolite kynurenine de-
serve special consideration in a discussion of possible
functional interactions between the two KP branches
in the brain of individuals with SZ. Postmortem analysis
reveals that kynurenine levels are elevated in the PFC of
in the same tissue.22The explanation for this nexus seems
unambiguous because the high Kmof KAT II and all
other cerebral kynurenine aminotransferases allows for
a proportional increase in KYNA formation when
kynurenine levels rise.58The cause of increased kynure-
nine levels in the brain of SZ patients is less clear. This
elevation, which is also seen in the cerebrospinal fluid59
and must therefore include changes in the extracellular
milieu, may be directly related to reduced KMO activity,
ie, to an accumulation of the enzyme’s substrate. Alter-
natively or quite possibly in addition, kynurenine levels
in the SZ brain might be elevated due to increased
activity of the biosynthetic enzymes tryptophan 2,3-
bly, these two enzymes, like the entire cerebral KP path-
way, are preferentially localized in glial cells,23,60–62and
newly produced kynurenine is readily liberated into the
Irrespective of the underlying enzymatic and cellular
mechanism(s), there are reasons to assume that the ob-
served increase in prefrontal KYNA levels plays a role
in the pathophysiology of SZ.22,64Within the PFC,
line and glutamate14,15,20by initially targeting and thus
reducing the activity of a7nAChRs.12Thus, increased
KYNA levels trigger or exacerbate the nicotinergic and
glutamatergic deficits, which have been credibly linked
to both cognitive dysfunctions and psychotic manifesta-
tions in humans (cf Introduction).1–3,65,66
The demonstration of distinct impairments in cerebral
KP metabolism in SZ, which are also observed in the
basal ganglia,67raises the prospect that more than one
KP enzyme could be targeted to provide clinical benefits
in the disease. This idea, which is an extension of our
recently proposed strategy to use selective KAT II inhib-
itors as cognition enhancers in SZ,68includes interven-
tions that are aimed specifically at normalizing KMO
and 3-HAO activity in the brain of patients. We are
currently testing this concept in relevant animal models
This study was in part supported by United States Public
Health Service grants (HD16596, MH83729, MH-
The authors wish to acknowledge and thank the past and
present members of the Maryland Brain Collection,
especially Drs Carol Tamminga, Robert Conley, and
William Carpenter, for diagnoses.
The Authors have declared that there are no conflicts of
interest in relation to the subject of this study.
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