Neural correlates of disrupted interpersonal cognition and clinical stage in patients with schizophrenia: An fMRI study

Abstracts / Neuroscience Research 71S (2011) e108–e415

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produced by this rather selective suppressing effect on the inhibitory transmission and the facilitating effect on excitatory neurons. Research fund: KAKENHI (20500357) and KAKENHI (21220006).

P3-s17 Neural correlates of disrupted interpersonal cognition and clinical stage in patients with schizophrenia: An fMRI study

doi:10.1016/j.neures.2011.07.1302

Yosuke Takano 1 , Hidenori Yamasue 1,2 , Noriaki Yahata 1,4 , Hideyuki Inoue 1 , Norichika Iwashiro 1 , Tatsunobu Natsubori 1 , Yuki Kawakubo 1 , Masaki Katsura 3 , Wataru Gonoi 3 , Mizuho Murakami 3 , Hiroki Sasaki 3 , Hidemasa Takao 3 , Osamu Abe 5 , Kiyoto Kasai 1,4

P3-s15 Electrophysiological properties of adult midbrain dopaminergic neurons of the mice treated with neuregulin1 as neonates Hisaaki Namba , Yusuke Takeda, Hiroyuki Nawa Dept. of Mol. Neurobiol., Brain Res. Inst., Niigata Univ., Niigata, Japan Neuregulin-1 (NRG1) is thought to contribute to neuronal development and schizophrenia neuropathology. Recently, we have reported the animals treated with NRG1 as neonate later exhibit hyper-dopaminergic states and behavioral deficits related to schizophrenia, such as reduced social interaction and enhanced sensitivity to the psychostimulants (Kato et al., 2011. Mol. Psychiatry 16: 307–320). Though, NRG1 receptor (ErbB4) is highly enriched in dopaminergic neurons in the midbrain, it is unknown whether ErbB4 stimulation in this population influences on their electrophysiological features and synaptic properties. Here, we chronically treated with an EGF core domain peptide of NRG1 (eNRG1) as neonate, and analyzed spontaneous firing activity and electrophysiological properties of dopaminergic neurons in the adult midbrain slices. As a result, spontaneous firing activity was enhanced especially in the ventral tegmental area. Patch-clamp recording revealed increased frequencies of miniature EPSCs, which suggests potentiated excitatory synaptic transmission in this neuronal population. Currently, we are analyzing molecular mechanisms underlying these electrophysiological traits. The enhancement of spike firing rates and synaptic inputs might be associated with the behavioral deficits of the NRG1-treated animals. doi:10.1016/j.neures.2011.07.1303

P3-s16 Abnormal white matter asymmetry in schizophrenia demonstrated by tract-based spatial statistics Jun Miyata 1 , Akihiko Sasamoto 1 , Katja Koelkebeck 3 , Kazuyuki Hirao 1 , Keita Ueda 1 , Ryosaku Kawada 1 , Shinsuke Fujimoto 1 , Yusuke Tanaka 1 , Manabu Kubota 1 , Nobukatsu Sawamoto 2 , Hidenao Fukuyama 2 , Hidehiko Takahashi 1 , Toshiya Murai 1 1

Dep. of Psychiatry, Grad. Sch. of Med., Kyoto Univ. Kyoto, Japan 2 Human Brain Res. Center, Grad. Sch. of Med., Kyoto Univ. Kyoto, Japan 3 Dep. of Psychiatry, Univ of Muenster, Germany Background: A number of studies have revealed morphological cortical asymmetry in the human brain, and reduction or inversion of such hemispheric asymmetry has been reported in schizophrenia. On the other hand, diffusion tensor imaging (DTI) studies have reported inconsistent findings concerning abnormal asymmetry of white matter integrity in schizophrenia. We aimed to investigate whether there is reduced or inverted asymmetry of white matter integrity in the whole brain in schizophrenia. Methods: Twenty-six right-handed schizophrenia patients and 32 matched healthy control subjects were investigated. DTI data were acquired and the fractional anisotropy (FA) image was created for each subject. Voxelwise analysis of FA data was performed using the tract-based spatial statistics. All FA images were normalized, and projected onto the symmetrical white matter template, and the laterality index (LI) of FA, determined by 2 × (left − right)/(left + right), was calculated. Both within-group and between-group statistical analyses of LI were performed. Results: Both patients and controls showed similar overall patterns of asymmetry. In the group comparison, patients showed significant reduction of LI in the external capsule (EC) and posterior limb of the internal capsule (PLIC). The EC cluster contained the uncinate fasciculus and inferior occipitofrontal fasciculus. The EC cluster revealed increased rightward asymmetry and the PLIC cluster showed reduced leftward asymmetry. Conclusion: As the brain asymmetries are considered to be genetically programmed, such an abnormal asymmetry in the connectivity of white matter tract would be a neurodevelopmental predisposition of this disorder. Research fund: KAKENHI (21890119 and 20691401), research fellowship from JSPS (PE 07550), a research grant from the Research Group for Schizophrenia sponsored by Astellas Pharma Inc., and a research grant from the Mitsubishi Pharma Research Foundation. doi:10.1016/j.neures.2011.07.1304

1

Dept Psych, Univ of Tokyo, Tokyo, Japan 2 Japan Science and Technology Agency, CREST, Tokyo, Japan 3 Dept Radiol, Univ of Tokyo, Tokyo, Japan 4 The Global Center of Excellence “Comprehensive Center of Education and Research for Chemical Biology of the Diseases”, Univ of Tokyo, Tokyo, Japan 5 Dept Radiol, Nihon Univ Sch of Med, Tokyo, Japan Patients with schizophrenia show deficits in interpersonal cognition, including abnormal performance on tasks targeting “theory of mind” (ToM) and empathy. Although previous neuroimaging studies have shown aberrant activations as neural correlates of disrupted ToM and empathy in patients with schizophrenia and at-risk mental state (ARMS), how and when such disruptions in these psychological processes emerge and progress is not fully investigated. In this functional magnetic resonance imaging (fMRI) study, the neural correlates of interpersonal cognition were investigated using short cartoons consisted of ToM, empathy and control conditions in subjects in ARMS, patients who had developed schizophrenia (Sz), and the age matched healthy subjects. The preliminary analysis in smaller sample revealed that ARMS (n = 9) and Sz (n = 9) subjects showed lower activity in the precuneus than healthy subjects (n = 16) during ToM condition compared with control condition (P < 0.01, uncorrected). Moreover, the decreased activation in precuneus was correlated with the high negative symptoms score in patients with Sz. During empathy condition compared with ToM, patients with Sz showed lower activity in medial prefrontal cortex, right amygdala and right inferior frontal gyrus than healthy subjects (P < 0.01, uncorrected). On the other hand, no significant difference of activation was observed between ARMS and healthy subjects in this contrast. These findings suggest that the two psychological processes were differently impaired depending on the clinical stages. The present study may contribute to developing the effective and objective biomarker related to early detection and prediction for developing psychosis. Research fund: JSPS Grant-in-Aid for Young Scientists (A), MEXT Strategic Research Program for Brain Science. doi:10.1016/j.neures.2011.07.1305

P3-s18 Comprehensive behavioral analysis of ENUinduced Disc1 mutant mice Hirotaka Shoji 1,2 , Keiko Toyama 1 , Yoshihiro Takamiya 3 , Shigeharu Wakana 4 , Yoichi Gondo 5 , Tsuyoshi Miyakawa 1,2,6 1

Div Sys Med Sci, ICMS, Fujita Health Univ, Toyoake 2 CREST, Saitama 3 Natl Mus Emerging Sci Innovation 4 Tech Dev Team Mouse Phenotype Anal, Riken BRC, Tsukuba 5 Mutagenesis Genomics Team, Riken BRC, Tsukuba 6 Ctr Gene Anal Behav, NIPS, Okazaki Disrupted in schizophrenia 1 (DISC1) is considered to be a candidate susceptibility gene for psychiatric disorders including schizophrenia, bipolar disorder, and major depression. Recent study reported that N-ethyl-Nnitrosurea (ENU)-induced mutations in exon 2 of mouse Disc1, resulting in amino acid exchange Q31L and L100P, caused the increase of depressionlike behavior in Q31L mutants mice and the schizophrenia-like behavior in L100P mutant mice, providing a potential animal models of psychiatric disorders. However, the possible remaining heterozygous mutations occurring in any flanking genes other than Disc1 itself might induce the behavioral abnormalities in the mutant mice as previously reported. Here, to confirm the effects of the mutations of Disc1-Q31L and Disc1-L100P on the behavioral phenotypes and to investigate the behaviors of the mutant mice in more detail, we backcrossed the mutant lines to C57BL/6JJcl by an additional two generations and analyzed the behaviors using our comprehensive behavioral test battery. Contrary to our expectations, Q31L mutant mice showed no significant behavioral differences from their wild-type littermates in any behavioral tests, including the Porsolt forced swim and tail suspension tests, commonly used tests for depression-like behavior. Also, L100P mutant mice exhibited no differences in almost all the behavioral tests, including prepulse inhibition test for measuring sensori-motor gating that is known to be impaired in schizophrenia patients. These results inconsistent with those of the previous studies may be explained by the differences in the genetic background of the subjects, laboratory environment, experimental protocols, and etc. Further behavioral studies under various experimental conditions will