Brain, Behavior, & Immunity - Health 22 (2022) 100446

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Imaging extra-striatal dopamine D2 receptors in a maternal immune
activation rat model
Arata Oh-Nishi a, b, c, *, Yuji Nagai a, Chie Seki a, Tetsuya Suhara a, Takafumi Minamimoto a,
Makoto Higuchi aabc

Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan
Division of Immune-Neuropsychiatry, Faculty of Medicine, Shimane University, Shimane, 693-8501, JapanRESVO Inc., Kawasaki, 210-007, JapanA R T I C L E I N F O

A B S T R A C T

Keywords:
Maternal immune activation
Schizophrenia
Dopamine D2 receptors
Dopamine
Anterior cingulate cortex
Poly I:C
Positron emission tomography
In vivo imaging[11C]FLB457
MIA rat model

Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents canbe induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased
striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic systemin the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R
abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in
vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior
cingulate cortex (ACC) region in the offspring showed signiﬁcantly reduced binding potential for [11C]FLB457, ahigh afﬁnity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of
dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC ofoffspring, similar to the neuronal pathology reported in patients with schizophrenia.

1. Introduction
Emerging literature from human epidemiological studies has provided evidence for the contribution of maternal infection to the etiology
of schizophrenia. Several studies have reported correlations between
inﬂuenza infection during pregnancy and an increased risk of psychiatricdisorders in offspring (Barr et al., 1990; Brown et al., 2004; Brown andMeyer, 2018; Kendell and Kemp, 1989; Mednick et al., 1988; Westergaard et al., 1999). Similar to inﬂuenza infection, other maternal infectious diseases have been also shown to increase this risk (Blomstrom
et al., 2012; Brown and Susser, 2002; Suvisaari et al., 1999), suggestingthat maternal immune activation (MIA) rather than a speciﬁc viral
infection increases the risk of schizophrenia in offspring.
MIA in pregnant experimental animals can be induced by injection ofsynthetic polyriboinosinic-polyribocytidilic acid (Poly I:C) or lipopolysaccaride (LPS), and these injections have been shown to cause
neurobehavioral abnormalities in the offspring (Brown and Meyer, 2018;
Hsiao et al., 2012; Hsiao et al., 2013; Meyer, 2013, 2014; Meyer et al.,2005; Patterson, 2009, 2011). These abnormalities were reportedly
ameliorated by antipsychotic administration (Casquero-Veiga et al.,2019; Ozawa et al., 2006; Piontkewitz et al., 2012; Roenker et al., 2011;
Romero et al., 2007; Scarborough et al., 2020; Zuckerman et al., 2003).
Dopamine D2 receptor (D2R) alterations have been reported in MIA
model rodents (Aguilar-Valles et al., 2020), and these alterations may
represent meaningful neuronal abnormalities, because almost all antipsychotics have an inhibitory effect on D2Rs. Nevertheless, the complete
picture of D2R alterations in the MIA model has not been clariﬁed to date.
In vivo imaging studies using positron emission tomography (PET)
have shown disturbances of extra-striatal D2Rs in patients with schizophrenia, and improvements in these disturbances are thought to beimportant for the treatment of schizophrenia (Takahashi et al., 2006). In
this study, we investigated extra-striatal D2R abnormalities in a Poly
I:C-induced MIA rat model by performing micro-positron emission tomography (micro-PET) with afﬁnity D2R radio-ligands such as [11C]
FLB457 and ex vivo neurochemical analyses.
2. Materials and methods
Described in Supplemental data.

* Corresponding author. Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba, 263-8555 Japan.
E-mail address: arata@resvo-inc.com (A. Oh-Nishi).
https://doi.org/10.1016/j.bbih.2022.100446
Received 24 January 2022; Accepted 4 March 2022
2666-3546/© 2022 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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A. Oh-Nishi et al.

β-actin as controls (bottom row) in the ACC of control (left lane in thepanel) and MIA (right lane in the panel) samples. The bar graph in Fig. 2Ashows D2R protein levels normalized by the β-actin level of the MIA
samples (ﬁlled bars; n ¼ 6) in the ACC in MIA rats was about 40% of thatin the controls (open bars; n ¼ 6), and the difference was statisticallysigniﬁcant (t-test; t(10) ¼ 2.4, P ¼ 0.037).
We also assessed DA turnover, a biochemical correlate of DA release(Murphy et al., 1996), by estimating the ratio of DA metabolites to DA in
vitro. We measured the amount of DA and its two major DA metabolites,
DOPAC and HVA, in ACC tissues excised from the two groups of rats. The
DA turnover in the ACC (i.e., the (DOPAC þ HVA)/DA ratio) in MIA rats
was signiﬁcantly higher than that in the controls (t-test, t (8) ¼ 3.0,
P < 0.05, n ¼ 5 each, Fig. 2B). Both DOPAC and HVA concentrations werealso signiﬁcantly higher in MIA rats (Fig. S3). These results suggest that
DA turnover is upregulated in the ACC of MIA rats.

3. Results
3.1. Localization of D2R dysfunction in the extra-striatal region of MIA
rats
Extra-striatal D2Rs in the MIA (n ¼ 5) and control (n ¼ 5) offspring
rats (postnatal weeks 12–13; see Supplemental data) were imaged by PET
with [11C]FLB457, a radioligand for extra-striatal D2Rs (Halldin et al.,1995). PET was performed during stable anesthetization of the rats.
Speciﬁc binding (BPND) of [11C]FLB457 in the extra-striatal region was
estimated by using a simpliﬁed reference tissue model with the cerebellum as the reference region (Lammertsma and Hume, 1996) (Fig. S1),
and parametric images of BPND were generated. Voxel-wise statisticalparametric mapping (SPM) analysis revealed a signiﬁcant decrease in[11C]FLB457 binding in a small cluster in MIA rats (uncorrected,
P < 0.01) (Fig. 1A), which corresponded to a part of Brodmann's area 24(BA24) of ACC (Hoover and Vertes, 2007). The reduction in BPND was
39% in comparison with the control rats (t(8) ¼ 4.19, P ¼ 0.003)(Fig. 1B). No BPND alterations were observed in any regions other thanBA24. Morphological comparisons based on MR images showed no signiﬁcant volume reduction in the ACC regions of the MIA rats (Fig. S2),
suggesting that the BPND reduction in the ACC regions of the MIA brains
was not accompanied by signiﬁcant volume changes.

4. Discussion
All three kinds of experimental data in this study, i.e., (1) in vivo
imaging with micro-PET of MIA rat brain ACC, (2) Western blot analysisof D2R proteins in MIA ACC, (3) HPLC-ECD measurement of dopamine
turnover in MIA ACC, unanimously point toward the presence of D2R
dysfunction in MIA ACC.
We identiﬁed BA24 of ACC as a single speciﬁc brain region in which
MIA induced reduction of [11C]FLB457 binding without volume reduction. [11C]FLB457 binding was considered to reﬂect both D2 and D3
receptor density (Halldin et al., 1995). In the rat cortical region, the D3RmRNA density was much lower than that of D2R mRNA, and the D2RmRNA density was as low as that of D3R mRNA in the cerebellum(Bouthenet et al., 1991); thus, [11C]FLB457 binding in the ACC mainly
reﬂects D2R density. Reduction of the [11C]FLB457 signal in BA24 in the

3.2. Reduction of D2R protein and up-regulation of DA turnover in the
ACC of MIA rats
Our PET data suggested a marked reduction in D2R expression in the
ACC of MIA rats. To verify this, we performed Western blot analysis toassess the level of D2R protein expression in ACC. The upper four panelsof Fig. 2A show western blots of D2R proteins (top row) together with

Fig. 1. Micro-PET with [11C]FLB457 analysis in thecontrol and MIA rats. (A) MRI images of the standard
rat brain are shown in grey scale, on which SPM images are overlaid in color to show the reduction in[11C]FLB457 binding in MIA rats in comparison withthat in control rats. The color bar in the panel shows
the scale of the SPM images, and a lighter color indicates a greater probability of a reduction in [11C]
FLB457 binding. (B) [11C]FLB457 binding potentials
in the ACC of MIA rats were about 39% lower thanthose in the control. **in the ﬁgure indicates P <0.01. Error bars denote mean  SEM. . (For interpretation of the references to color in this ﬁgurelegend, the reader is referred to the Web version ofthis article.)2

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Fig. 2. Reduction of the D2R expression level andabnormal DA turnover in MIA rats. (A) The upper twopanels show western blots of D2R proteins together
with β-actin as controls in the ACC of the control and
MIA samples. The D2R- and β-actin-speciﬁc bands
were at 75k and 38k, respectively, on the SDS-PAGE
gel. The concentration ratios of D2R to β-actin
indexed to healthy controls show a reduction in the
ACC of MIA rats. Data are expressed as percentage ofthe value in the control rats. (B) The ratio of themetabolites (DOPAC þ HVA)/DA in the ACC and TC
in MIA rats was signiﬁcantly greater than that in thecontrol. * in the ﬁgure indicates P < 0.05. Error bars
denote mean  SEM.

anti-psychotic drugs (i.e,. haloperidol) has been reported to lead to an
enlarged and elongated GABAergic terminal on pyramidal neurons in the
medial prefrontal cortex (mPFC) of rats (Vincent et al., 1994). Althoughbehavioral improvements in the abnormalities in the MIA rodent modelby administration of anti-psychotic drugs (Ozawa et al., 2006; Zuckerman et al., 2003) has been thought to be mediated by normalization of
dopamine excess in the striatum, restoration of GABAergic interneuronal
dysfunction in ACC could also contribute to it.
We conclude that MIA causes a reduction in D2 receptors withabnormal dopaminergic transmission in the ACC in the rodent model.
The micro-PET ﬁndings were similar to the in vivo imaging ﬁndings forpatients with schizophrenia. Therefore, D2 receptor alteration in the ACC
may be an important ﬁnding for cortical pathology and for understanding
the pathogenesis of schizophrenia.

MIA rat could be due to signal spillover from the striatum where thesignal was very high. However, the results of western blotting support adecrease in [11C]FLB457 binding in the ACC, reﬂecting a reduction in
D2R expression in MIA rats.
HPLC-ECD measurement of dopamine and its metabolites showedthat dopamine turnover was enhanced in MIA rat ACC, suggesting that
DA transmission is up-regulated. Pyramidal neurons in BA24 can show
excitatory activity in the ventral tegmental area (VTA) through directconnections (Gabbott et al., 2005; Hoover and Vertes, 2007). Pharmacological stimulation of D2R in the medial prefrontal cortex, including
BA24, inhibits the excitatory glutamate drive on DA neurons in the VTA(Harte and O'Connor, 2004). Thus, a reduction of D2R in BA24 of MIA rat
may cause disinhibition of DA neurons in VTA and thereby induce
upregulation of DA release in the cortical regions. This possibility should
be investigated in future studies. Immunoreactivity of D2 receptors is
reduced in the pre-frontal cortex of MIA mice and increased in the nucleus accumbens (Meyer et al., 2008; Vuillermot et al., 2010). D2 receptor binding is reduced in the striatum of MIA mice (Ozawa et al.,2006). Prenatal Poly IC injection at gestational day (GD) 15 produced
enhanced release of DA from rat striatal explants (Zuckerman et al.,2003). Mouse model studies showed that DA and its metabolites werealso altered in other brain regions (i.e., pre-frontal cortex, globus pallidus, and nucleus accumbens) (Giovanoli et al., 2013; Winter et al.,2009). The present results, together with the ﬁndings of previous studies
in MIA rodent models described above, indicate an outline of the pathophysiology in this model—enhanced DA transmission brains.
D2R alterations in the cortical regions of patients with schizophrenia
have been investigated by PET/SPECT studies using high-afﬁnity D2R
radio-ligands such as [11C]FLB457, [123I]epidepride, or [18F]fallypride;
the results showed alterations of radio-ligand binding in various regions(Buchsbaum et al., 2006; Glenthoj et al., 2006; Suhara et al., 2002; Talvik
et al., 2003; Tuppurainen et al., 2003; Yasuno et al., 2004). Our MIA rat
model ﬁndings are similar to those described in several reports that noted
reduction of D2R binding in the ACC of patients with schizophrenia by
PET studies using [11C]FLB457 and [18F]fallypride (Buchsbaum et al.,2006; Suhara et al., 2002).
Because D2R is abundant in the interneurons in ACC (Xu and Zhang,2015), reduced D2R binding may reﬂect an alteration in the interneurons
in this region. Indeed, MIA produces GABAergic interneuronal dysfunction in the rodent model forebrain (Canetta et al., 2016; Dickerson et al.,2014; Nakamura et al., 2019). Interestingly, administration of

Declaration of competing interest
A. O-N. is CEO & CTO of RESVO Inc. and owns more than 5% of theshares of RESVO Inc., but had no role in the study design, data collection
and analysis, decision to publish, or preparation of the manuscript. This
disclosure does not alter our adherence to Brain, behavior and immunity
publication policy. The other authors have no competing interests to
declare.
Acknowledgements
We are grateful to late Prof. P. Patterson (Caltech) and Dr. N. Suzuki(Kitasato Univ.) for their comments on an earlier version of the manuscript, H. Tomizawa (Chiba Univ.) for technical assistance, and J. Ko(Caltech) for technical advice. This work was supported by KAKENHI
23700432 (to A.O-N), Japan Advanced Molecular Imaging Program from
the Ministry of Education, Culture, Sports, Science and Technology(MEXT), Japan. A part of this work was carried out under the Brain
Mapping by Integrated Neurotechnologies for Disease Studies (Brain/
MINDS) by MEXT, Japan.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.bbih.2022.100446.

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