nr3a nmda receptor subunit mrna expression in schizophrenia, depression and bipolar disorder

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Schizophrenia Research 71 (2004) 361–370

NR3A NMDA receptor subunit mRNA expression in

schizophrenia, depression and bipolar disorder

Helena T. Mueller*, James H. Meador-Woodruff

Neuroscience Graduate Program, Department of Psychiatry, Mental Health Research Institute, University of Michigan Medical School,

205 Zina Pitcher Place, Ann Arbor, MI 48109-0720, USA

Received 19 November 2003; received in revised form 9 February 2004; accepted 13 February 2004

Available online 13 April 2004

Abstract

Growing evidence suggests that NMDA receptor (NMDAR) dysfunction may be involved in schizophrenia. The NMDAR is

a multimeric assembly derived from seven different genes (NR1, NR2A–2D and NR3A–3B). While region-specific changes in

the expression of most NMDAR subunits have been reported in schizophrenia, possible abnormalities of NR3A expression

have not been investigated. Both electrophysiological and anatomical data in rodents, however, suggest that NR3A subunits

could play a role in this disorder. In this study, we measured NR3A transcript levels in the dorsolateral prefrontal cortex

(DLPFC) and inferior temporal neocortex in the brains of people with schizophrenia, bipolar disorder, depression, and a

comparison group. This transcript was elevated by 32% in schizophrenia relative to controls, but only in the DLPFC and not

inferior temporal cortical regions. Interestingly, this effect was restricted to gyral aspects of the DLPFC and did not involve

sulcal areas. NR3A mRNAwas significantly decreased by 12% in bipolar disorder relative to the comparison group in DLPFC,

although there were no gyral versus sulcal differences. As was the case in schizophrenia, no changes in NR3A expression were

observed in the inferior temporal cortex in bipolar disorder. These data indicate that the NR3A subunit is abnormally expressed

in both schizophrenia and bipolar disorder.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Glutamate receptor; Psychosis; Prefrontal cortex; Temporal cortex; Development

1. Introduction NMDAR antagonists such as phencyclidine (PCP)

Glutamatergic dysfunction has been implicated in

the pathophysiology of schizophrenia; in particular, it

has been hypothesized that the NMDA receptor

(NMDAR) may be dysregulated in this illness (Olney

et al., 1999). This is based upon studies revealing that

0920-9964/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.schres.2004.02.016

* Corresponding author. Tel.: +1-734-936-2061; fax: +1-734-

647-4130.

E-mail address: [email protected] (H.T. Mueller).

and ketamine can induce both positive and negative

psychotic symptoms in normal individuals, and exac-

erbate these symptoms in schizophrenia (Olney et al.,

1999). Furthermore, agonists of the glycine/D-serine

coagonist site of the NMDAR can improve some of

the negative symptoms in this disorder (Goff and

Coyle, 2001).

The NMDAR is a heteromeric complex comprised

of subunits derived from seven different genes (NR1,

NR2A–2D and NR3A–3B) (Ciabarra et al., 1995;

H.T. Mueller, J.H. Meador-Woodruff / Schizophrenia Research 71 (2004) 361–370362

Hollman and Heinemann, 1994; Sucher et al., 1995).

Both the obligate NR1 subunit, which can be alterna-

tively spliced to produce eight different isoforms, and

the NR2 subunits contribute to the molecular diversity

of NMDARs by generating receptors with unique

properties that alter the activity, sensitivity and/or

efficiency of NMDARs (Hollman and Heinemann,

1994). Subunit composition is thus an important level

of NMDAR regulation, and NMDAR dysfunction may

reflect changes in receptor stoichiometry due to

changes in the expression of particular NMDAR sub-

units. In recent years, region-specific changes in

NMDAR subunits and binding sites have been reported

in schizophrenia (Dracheva et al., 2001; Gao et al.,

2000; Meador-Woodruff and Healy, 2000), consistent

with NMDAR disturbances in this illness.

The NR3A subunit has not yet been investigated

in schizophrenia. In vitro studies indicate that

NR3A is a modulatory subunit that can alter

NMDA receptor activity and function (Chan and

Sucher, 2001; Chatterton et al., 2002; Ciabarra et

al., 1995; Das et al., 1998; Sucher et al., 1995).

Electrophysiological studies have shown that the

NR3A subunit can coassemble with NR1 and

NR2A or NR2B to form functional NMDARs with

decreased NMDAR activity and decreased Ca2+ flux

(Ciabarra et al., 1995; Sucher et al., 1995); mice

lacking the NR3A subunit show enhanced NMDA

receptor activity (Das et al., 1998). Interestingly,

NR3A can also coassemble with NR1 subunits to

form a nonconventional NMDAR that functions as

an excitatory glycine receptor, at which glycine

alone elicits a physiologically relevant current that

is impermeable to Ca2+ (Chatterton et al., 2002).

Pharmacological profiles matching NR1/NR3A

receptors have been observed in cortical neurons,

suggesting that these receptors exist in vivo (Chat-

terton et al., 2002). NMDAR activity and function

Table 1

Summary of subject characteristics

Schizophrenia Bipolar d

N 15 15

Age (years) 44.2 (25–62) 42.3 (25

Sex 9 M, 6 F 9 M, 6 F

PMI (h) 33.7 (12–61) 32.5 (13

Tissue pH 6.1 (5.8–6.6) 6.2 (5.8–

Side of brain studied 6 R, 9 L 8 R, 7 L

can also be modulated at the level of subunit

phosphorylation; NR3A can influence the phosphor-

ylation state of the NR1 subunit by its interaction

with protein phosphatase 2A (PP2A), which causes

dephosphorylation of Ser 897 on NR1 (Chan and

Sucher, 2001). Given these findings, abnormalities

of NR3A expression may contribute to NMDAR

disturbances implicated in schizophrenia.

Additional support for a possible role of NR3A

in schizophrenia comes from findings on its tempo-

ral and anatomical distribution in the rodent brain

(Ciabarra et al., 1995; Sucher et al., 1995). NR3A is

a developmentally regulated subunit, and there is

evidence that developmental abnormalities occurring

during the second trimester of pregnancy may play

a role in the pathophysiology of schizophrenia

(Marenco and Weinberger, 2000). In animal models,

rat hippocampal lesions on postnatal day 7 lead to

behavioral abnormalities similar to some of the

symptoms of schizophrenia (Lipska and Weinberger,

2002; Wood et al., 1997). Interestingly, NR3A is

highly expressed in the rat brain during develop-

ment, peaking around postnatal day 7 and subse-

quently decreasing over time (Ciabarra et al., 1995;

Sucher et al., 1995). We have found that NR3A is

robustly expressed in the human fetal cortex during

the second trimester (Mueller and J.H., 2003), and

is expressed in regions often associated with schizo-

phrenia, including the prefrontal cortex, thalamus,

and hippocampus.

We hypothesize that the NR3A subunit may play

an important role in pathological processes related to

NMDAR dysfunction and/or developmental abnor-

malities implicated in schizophrenia. Accordingly,

we measured NR3A transcript levels in the dorsolat-

eral prefrontal cortex (DLPFC) and temporal neocor-

tex in schizophrenia, bipolar disorder, depression and

a comparison group.

isorder Major depression Controls

15 15

–61) 46.4 (30–65) 48.1 (29–68)

9 M, 6 F 9 M, 6 F

–62) 27.5 (7–47) 23.7 (8–42)

6.5) 6.2 (5.6–6.5) 6.3 (5.8–6.6)

6 R, 9 L 7 R, 8 L

Fig. 1. Expression patterns of NR3A mRNA in DLPFC and inferior

temporal neocortex. High-power magnification of NR3A expression

in the DLPFC (top panel) and inferior temporal neocortex (lower

panel) showing isodense banding patterns. In the DLPFC, four

isodense bands were identified, and three isodense bands were seen

in the inferior temporal neocortex. The right side of the images

indicate the isodense bands (a–d or a–c), while the left side

identifies the conventional six cortical layers. Scale bar=1 mm.

H.T. Mueller, J.H. Meador-Woodruff / Schizophrenia Research 71 (2004) 361–370 363

2. Methods

2.1. Subjects

Sixty subjects from the Stanley Foundation Neu-

ropathology Consortium were used for this study,

consisting of 15 nonpsychiatrically ill control individ-

uals, 15 patients with schizophrenia, 15 with major

depressive disorder, and 15 with bipolar disorder. The

groups were matched for age, sex, pH and postmor-

tem interval. A detailed description of this collection

was been published (Torrey et al., 2000), and a

summary of subject characteristics is shown (Table

1). Fresh frozen blocks of tissue from these regions

were cryostat sectioned (14 Am), mounted onto slides,

stored at �80 jC until studied and provided to us. For

this study, the DLPFC and temporal neocortex were

examined.

2.2. In situ hybridization

A NR3A riboprobe was synthesized from a plas-

mid containing a specific NR3A subclone [NCBI

GeneBank accession number AJ416950, nucleotide-

coding region (2104–2689)]. The NR3A sequence

was amplified by PCR from a human fetal brain

cDNA library, inserted into pCR4Blunt-TOPO vector

(Zero Blunt TOPO PCR cloning kit, Invitrogen,

Carlsbad, CA) and the final product confirmed by

sequencing. The NR3A riboprobe was prepared by

labeling with 100 ACi of [33P] UTP, 2.0 Al 5X

transcription buffer, 1.0 Al 0.1 M dithiothreitol

(DTT), 1.0 Al each of 10 mM ATP, CTP, GTP, 2.0

Al linearized plasmid, 0.5 Al RNase inhibitor and 1.5

Al SP6 RNA polymerase, and incubating this reaction

mixture for 2 h at 37 jC. One microliter DNase

(RNase-free) was then added and incubated for an

additional 15 min at room temperature. Labeled probe

was then purified with a Micro Bio-Spin P-30 Tris

Spin Column (Bio-Rad Laboratories). Finally, 1

Al DTT was added to a final concentration of 0.01 M.

Slides were removed from �80 jC storage and

fixed in 4% formaldehyde for 1 h at room tempera-

ture, followed by three rinses in 2X SSC (300 mM

NaCl, 30 mM sodium citrate pH 7.2). Next, they were

acetylated (0.1 M triethanolamine pH 8.0:acetic an-

hydride (400:1 vol/vol) for 10 min, washed in 2X SSC

for 10 min, and dehydrated in graded alcohols. 5�106

cpm of radiolabeled probe in 500 Al of 50% hybrid-

ization buffer (50% formamide, 10% dextran sulfate,

3X SSC, 50 mM Na2HPO4, 1X Denhardt’s solution,

100 ug/ml yeast tRNA, 10mM DTT) was placed on

each slide, covered and incubated overnight at 55 jC.The following day, cover slips were removed and

slides were washed in 2X SSC for 5 min at room

temperature followed by RNase treatment (200 Ag/ml

in 10 mM Tris–HCl pH 8.0, 0.5 M NaCl) at 37 jC for

30 min. Slides were then washed twice in 2X SSC for

15 min, once in 1X SSC for 15 min at room

temperature, followed by two consecutive washes in


0.5X SSC for 1 h at 55 jC, and a final wash in 0.5X

SSC at room temperature for 15 min. The slides were

then dehydrated in graded alcohols and apposed to

film (Kodak Biomax MR-1, New England, Nuclear,

Boston, MA) for 2 months.

2.3. Data analysis

Images were acquired by digitizing in situ hy-

bridization films with a PC-based CCD imaging

system. Image analysis was performed using Scion

Image Beta 3b. Gray scale values (GSV) were

obtained from regions of interest, corrected for

background by subtracting GSV values from adja-

cent white matter, and converted into optical density

(O.D.) values, which are linear with respect to

concentration. Values from two sections per subject

were averaged and used for statistical analysis. For

both the DLPFC and temporal neocortex, we iden-

tified reproducible patterns of labeling in isodense

bands (Fig. 1). In the DLPFC, we identified four

Fig. 2. Gyral versus sulcal expression of the NR3A subunit in DLPFC an

mRNA in the gyrus and sulcus of the DLPFC (left panels) and inferior te

gyrus differs from that observed in the sulcus in both DLPFC and ITG. S

isodense bands. In the temporal neocortex, we iden-

tified three isodense bands in the inferior temporal

gyrus (Fig. 1). Data were analyzed by analysis of

variance with post hoc, analyses by Tukey’s HSD.

Alpha=0.05 for all tests of significance.

3. Results

NR3A mRNA was found in both the dorsolateral

prefrontal and inferior temporal neocortex. As previ-

ously reported in rodent, relatively dense labeling was

noted in an isodense band corresponding to layer V in

both cortical regions. Modest labeling was also ob-

served in a superficial isodense band corresponding to

layer II, but only in the DLPFC and not in the

temporal neocortex (Fig. 1). At a macroscopic level,

there appeared to be differences in expression between

gyral and sulcal regions in the isodense band

corresponding to layer V for both the DLPFC and

inferior temporal neocortex (Fig. 2).

d inferior temporal neocortex. Low-power magnification of NR3A

mporal cortex (ITG, right panels). The pattern of expression in the

cale bar=1 mm.


In the DLPFC (Fig. 3), main effects were found for

diagnosis (F=17.3, df=3440, p<0.000001), isodense

band (F=340, df=1440, p<0.000001), and when com-

paring gyrus versus sulcus expression (F=27.0,

df=1440, p<0.000001). Post hoc testing revealed that

the main effect for diagnosis was due to the subjects

with schizophrenia having 32% higher levels than

controls ( p=0.00007) and the bipolar group having

12% lower levels compared to controls ( p=0.000008).

Fig. 3. NR3A expression in the DLPFC in schizophrenia, depression and

mRNA levels in the DLPFC in schizophrenia, depression, bipolar disorder,

the gyrus and sulcus of the DLPFC. NR3A mRNA levels were significantl

hoc analysis revealed that NR3Awas specifically increased only in the gyr

mRNA was decreased in both the gyrus and sulcus

In addition, the schizophrenia group had higher

mRNA levels than both the bipolar ( p=0.000008)

and depression ( p=0.000009) groups. A significant

gyrus versus sulcus by diagnosis interaction was also

found (F=3.0, df=3440, p<0.03). Post hoc tests

revealed that this was due to patients with schizophre-

nia having significantly higher expression in the gyrus

( p=0.00006), but not in the sulcus ( p=0.9) compared

to the controls.

bipolar disorder. In situ hybridization was used to determine NR3A

and a comparison group. We examined four isodense bands in both

y increased in schizophrenia and decreased in bipolar disorder. Post

us and not in the sulcus in schizophrenia. In bipolar disorder, NR3A


In the inferior temporal neocortex (Fig. 4), there was

a main effect for diagnosis (F=3.7, df=3323, p<0.01),

isodense band (F=442, df=2323, p<0.000001) and

gyrus versus sulcus (F=7.2, df=1323, f<0.008). Post

hoc analysis indicated that the main effect for diag-

nosis was due to the bipolar group differing signifi-

cantly from both the depression and schizophrenia

groups. None of the psychiatric illness groups dif-

fered from control levels, however. In this cortical

region, there was no diagnosis by gyrus versus sulcus

effect.

Fig. 4. NR3A expression in the ITG in schizophrenia, depression and b

mRNA levels in the ITG in schizophrenia, depression, bipolar disorder, and

gyrus and sulcus of the ITG and found no significant changes in NR3A m

4. Discussion

In this study, in DLPFC we found increased NR3A

mRNA expression in schizophrenia and a decrease in

bipolar disorder relative to controls, while no differ-

ences were observed in inferior temporal neocortex

for any diagnostic group compared to controls. The

increased DLPFC expression in schizophrenia was

restricted to the gyral area of this cortical region,

while the decrease in bipolar disorder was seen

throughout the DLPFC.

ipolar disorder. In situ hybridization was used to determine NR3A

a comparison group. We examined three isodense bands in both the

RNA levels in any diagnostic group relative to controls.

Schizophrenia Research 71 (2004) 361–370 367

4.1. NR3A expression in schizophrenia

The NMDAR hypothesis of schizophrenia is based

in large part on findings that NMDAR antagonists can

lead to the induction or exacerbation of both positive

and negative symptoms, as well as cognitive deficits

observed in schizophrenia (Olney et al., 1999). While

this model is widely cited, the mechanism by which

decreased NMDAR activity may occur in this illness

remains unknown. One possibility is that alterations

occur at the receptor level, due to changes in subunit

composition. Relatively few studies have examined

the expression of NMDAR subunits in the DLPFC in

schizophrenia. In a study examining five of the

NMDAR subunits (NR1 and NR2A–NR2D), Akbar-

ian et al. (1996) found no overall differences in the

mRNA levels for any of these subunits; however, they

did report a 53% increase in the relative proportion of

NR2D subunit to the other NR2 subunits in schizo-

phrenia in the prefrontal cortex. In another study, NR1

expression was reported to be significantly decreased

in superior frontal cortex in schizophrenia (Sokolov,

1998). More recently, NR1 expression was reported to

be significantly elevated in the lateral prefrontal

cortex in schizophrenia (Dracheva et al., 2001); con-

sistent with this, glycine binding, which is associated

with the NR1 subunit, was reported to be significantly

increased in the frontal cortex in this disorder (Ishi-

maru et al., 1992). The apparent discrepancies of these

findings could be due to several factors including age

of subjects, specific cortical region examined, or

differences in techniques. Expression of these subu-

nits in other brain regions has also been examined,

and these studies suggest expression of certain

NMDAR subunits may change in schizophrenia in a

region-specific manner (Meador-Woodruff and Healy,

2000).

The addition of NR3A subunits to NR1/NR2 con-

taining receptors is similar to the effects of PCP or

ketamine, in that NR3A decreases NMDAR activity

(Ciabarra et al., 1995; Sucher et al., 1995). This

suggests that upregulation of the NR3A subunit could

provide a neurochemical basis for decreased NMDAR

tone in schizophrenia. To begin to address this, we

measured NR3A transcript expression in schizophre-

nia. We focused on the DLPFC because the negative

symptoms and cognitive deficits induced by NMDAR

antagonists are associated with impairments in

H.T. Mueller, J.H. Meador-Woodruff /

DLPFC function (Bunney and Bunney, 2000; Mog-

haddam et al., 1997). Our results indicate that NR3A

mRNA levels in DLPFC are significantly elevated in

schizophrenia relative to a comparison group. This

suggests that NR1/NR2/NR3A containing NMDARs

may be upregulated in the DLPFC in this illness,

which in turn could lead to decreased NMDAR

activity in the DLPFC.

In addition to decreased NMDAR activity, other

properties associated with these receptors may indi-

rectly alter NMDAR function and glutamatergic neu-

rotransmission. For example, NR1/NR2/NR3A recep-

tors also have reduced Ca2+ influx, and because Ca2+

is a critical intracellular signaling molecule, multiple

calcium-dependent intracellular pathways could be

significantly disturbed. In support of this, there are

accumulating data suggesting Ca2+ signaling and/or

homeostasis is abnormal in schizophrenia (Lidow,

2003). Decreasing Ca2+ influx by blocking calcium

channels has been found to worsen certain psychotic

symptoms (Lidow, 2003), and a number of Ca2+-

associated proteins have been found to be decreased

in the DLPFC in schizophrenia including GAP-43,

DARPP-32, and Reelin (Lidow, 2003). DARPP-32 is

of particular interest because it is tightly interconnec-

ted to the NMDAR (Greengard et al., 1999). DARPP-

32 phosphorylation is dependent on NMDAR-regu-

lated Ca2+ flux, and phosphorylated DARPP-32 in

turn regulates NR1 phosphorylation. Interestingly,

NR3A can also influence NR1 phosphorylation by

activating PP2A. The state of NR1 phosphorylation is

critical for efficient NMDAR function.

In addition, NR3A levels during brain develop-

ment are high. NR3A expression peaks early, and

rapidly declines with age, reaching much lower levels

in the adult brain (Ciabarra et al., 1995; Sucher et al.,

1995). In schizophrenia, the NR3A subunit may not

be developmentally downregulated, but rather contin-

ues to be expressed at higher than normal levels in the

DLPFC, resulting in prolonged NMDAR dysfunction

throughout development. The second trimester is

considered a critical time in brain development for

such changes to occur and exert an effect, and

recently, we have shown that NR3A is highly

expressed during the second trimester in human fetal

brain (Mueller and J.H., 2003). A number of devel-

opmental abnormalities have been described in the

DLPFC in schizophrenia (Marenco and Weinberger,


2000) including decreased dendritic spine density

(Garey et al., 1998; Glantz and Lewis, 2000; Marenco

and Weinberger, 2000). This is notable because den-

dritic growth is mediated in part by NMDAR activity

(Burgoyne, 1993). For example, mice deficient in the

NR3A subunit display enhanced dendritic spine den-

sity (Das et al., 1998). While speculative, it is possible

that abnormally persistent NR3A expression may

participate in the reduction of dendritic spine density

observed in the DLPFC in schizophrenia.

While a convergence of data suggests NR1/NR2/

NR3A receptors are increased in schizophrenia, it is

possible that NR1/NR3A-containing receptors are also

assembled and increased in schizophrenia. NR1/

NR3A-containing receptors are unique in that they

function as excitatory glycine receptors (Chartterton et

al., 2002). Unlike conventional NMDARs, these

receptors respond only to glycine and are unrespon-

sive to glutamate. Coagonists of the conventional

NMDARs, like D-serine, actually inhibit the glycine-

activated currents of these receptors. These receptors

are also insensitive to Mg2+, suggesting they are not

voltage-dependent, unlike most other NMDARs. Sim-

ilar to NR1/NR2/NR3A receptors, NR1/NR3A recep-

tors exhibit decreased Ca2+ influx. Pharmacological

profiles matching NR1/NR3A containing NMDARs

have been reported in the rodent cortex (Chartterton et

al., 2002). Although we cannot exclude the possibility

that NR1/NR3A receptors are upregulated in schizo-

phrenia, an increase in NR1/NR2/NR3A-containing

receptors is most consistent with an NMDAR hypo-

function model.

We also measured NR3A expression in the infe-

rior temporal neocortex, and found NR3A transcript

levels were not altered in schizophrenia, suggesting

that changes in NR3A mRNA expression may be

region-specific.

4.2. NR3A expression in mood disorders

In recent years, a number of studies have reported

changes in glutamatergic molecules in various brain

regions in the mood disorders (Vawter et al., 2000).

However, as with schizophrenia, these data have often

been inconsistent. Recently, both decreased NMDAR

binding using [3H]-MK801, and decreased NR1

mRNA have been reported in the hippocampus in

bipolar disorder (Law and Deakin, 2001; Scarr et al.,

2003), while no changes were reported for the other

two ionotropic glutamate receptors (AMPA and kai-

nate) (Dean et al., 2001; Scarr et al., 2003), suggesting

that there may be NMDAR-specific abnormalities

associated with bipolar disorder in the medial temporal

lobe. While there are indications of frontal cortical

abnormalities in bipolar disorder, there has only been

one study examining glutamate receptors in the

DLPFC in bipolar disorder, revealing no changes in

AMPA, kainate or NMDA receptor binding (Dean et

al., 2001). No studies have examined NMDAR subunit

expression in this disorder in DLPFC. In this study, we

examined NR3A expression in both depression and

bipolar disorder in the DLPFC. We found that while

NR3A expression did not significantly change in

depression, NR3A mRNA levels were significantly

decreased in the DLPFC in bipolar disorder. This may

indicate that NR1/NR2/NR3A receptors are decreased,

suggesting NMDAR activity may be increased, along

with increased Ca2+ influx. Such increases may en-

hance DLPFC activity; consistent with this, a recent

study reported that DLPFC activation during a verbal

fluency task was higher in subjects with bipolar

disorder relative to a control group (Curtis et al.,

2001). On the other hand, subjects with schizophrenia

showed attenuated frontal activation while performing

this same task. Similar to schizophrenia, NR3A ex-

pression was not altered in the inferior temporal

neocortex in either depression or bipolar disorder.

A confounding variable in clinical studies such as

this is subject exposure to medication. There are

numerous studies showing that psychiatric medica-

tions can alter the expression of various proteins and

transcripts. However, the effects are complex and vary

depending on drug, subunit, and region studied. Cur-

rently, the effects of these drugs on NR3A expression

are unknown. Nonetheless, our findings in schizophre-

nia are consistent with both the NMDAR hypofunction

model and prevailing neurodevelopmental hypotheses

of schizophrenia, suggesting that changes in NR3A

expression may be related to the pathophysiology of

schizophrenia and not past drug treatment.

5. Conclusion

We measured NR3A transcript expression in the

DLPFC and the inferior temporal neocortex in


schizophrenia, depression, and bipolar disorder and

found that NR3A mRNA levels were significantly

altered in the DLPFC in both schizophrenia and

bipolar disorder, but not in the inferior temporal

neocortex. Interestingly, we found that NR3A ex-

pression was elevated in schizophrenia, but de-

creased in bipolar disorder, suggesting there are

distinct neurochemical abnormalities associated with

these disorders.

Acknowledgements

This work was supported by MH650101 (HTM)

and MH53327 (JMW). The authors gratefully ac-

knowledge the assistance of Patricia Tessler, PhD and

Monica Beneyto, PhD. Postmortem brains were

donated by The Stanley Medical Research Institute’s

Brain Collection courtesy of Drs. Michael B. Knable,

E. Fuller Torrey, Maree J. Webster, Serge Weis, and

Robert H. Yolken.

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