Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.
Schizophrenia is a common neuropsychiatric disorder affecting 0.5–1% of the general population worldwide. This disease is characterized by psychosis and profound disturbances of cognition, emotion and social functioning. The pathophysiology of schizophrenia is still unclear; however, this disease is highly heritable1 and several intermediate phenotypes such as neurocognitive dysfunction, abnormal brain morphology and deficits in prepulse inhibition (PPI) of the startle response are known to be useful to identify susceptibility genes for schizophrenia.2, 3
The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide, which is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family. It exerts multiple activities as a neurotransmitter or neuromodulator via three heptahelical G-protein-linked receptors, one PACAP-specific (PAC1) receptor and two receptors that are shared with VIP (VPAC1 and VPAC2).4, 5, 6 PACAP induces cyclic AMP accumulation through activation of these receptors.4, 5, 6 We generated mice lacking the PACAP gene (PACAP−/−); these mice had profound behavioral abnormalities including hyperactivity and explosive jumping in an open field, increased novelty-seeking behavior and deficits in PPI.7, 8 In addition, the PACAP gene is located on 18p11, which linkage studies have suggested as a locus for schizophrenia and bipolar disorder.9 Although previous studies indicated that the PACAP gene could be a good candidate gene for schizophrenia, only one preliminary study has examined a possible association with schizophrenia and reported negative results.10 Here, we present data demonstrating a possible association between PACAP-PAC1 signaling and schizophrenia, using a multidisciplinary approach in both humans and rodents.
Materials and methods
Subjects for the clinical association study were 804 patients with schizophrenia (51.1% males with a mean age of 44.2 years (s.d. 14.5) and a mean age of onset of 24.8 years (s.d. 8.8)) and 967 healthy controls (47.7% males with a mean age of 40.4 years (s.d. 16.1)). All the subjects were biologically unrelated Japanese. Three hundred and fifty-one patients with schizophrenia and 518 controls were from Tokyo Metropolitan (the east part of Japan), and 453 patients with schizophrenia and 449 controls were from Aichi prefecture (the central part of Japan). Patients were recruited at the National Center Hospital of Mental, Nervous, and Muscular Disorders; Nagoya University Hospital; Showa University Hospital and hospitals related to Department of Psychiatry, Nagoya University Graduate School of Medicine or Department of Psychiatry, Showa University School of Medicine. Healthy controls, including hospital and institutional staff, were recruited from local advertisements in Tokyo and Aichi. Magnetic resonance (MR) measurements and neurocognitive tests were performed only on some subjects (MR measurements: 81 patients with schizophrenia and 201 healthy controls; neurocognitive tests: 62 patients with schizophrenia and 139 healthy controls), all of whom were recruited at National Center of Neurology and Psychiatry. Demographic information for the subjects receiving MR measurements and neurocognitive tests is shown in detail in Supplementary Table 1 and Figure 1b. Consensus diagnosis was made for each patient by at least two trained psychiatrists, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria, based on clinical interview and other available information including medical records and other research assessments. No patient was diagnosed by medical records alone. Controls were healthy volunteers who had no current or past contact to psychiatric services. After a description of the study, written informed consent was obtained from every subject. The study protocol was approved by institutional ethics committees.
Venous blood was drawn from subjects and genomic DNA was extracted from whole blood according to standard procedures. Seven single nucleotide polymorphisms (SNPs) in the PACAP gene and three SNPs in the PAC1, VPAC1 and VPAC2 genes were genotyped using the TaqMan 5′-exonuclease allelic discrimination assay, as described previously.11, 12 Primers and probes for the detection of the SNPs are available on request. Statistical analysis of genetic association studies was performed using SNPAlyse (DYNACOM, Yokohama, Japan). The presence of Hardy–Weinberg equilibrium was examined by using the χ2 test for goodness of fit. Allele distributions between patients and controls were analyzed by the χ2 test for independence. All P-values reported are two-tailed. Statistical significance was defined as P<0.05.
All MR studies were performed on a 1.5 T Siemens Magnetom Vision plus system (Siemens, Erlangen, Germany). A three-dimensional volumetric acquisition of a T1-weighted gradient echo sequence produced a gapless series of 144 sagittal sections using an MPRage sequence (TE/TR, 4.4/11.4 ms; flip angle, 15°; acquisition matrix, 256 × 256; 1NEX, field of view, 31.5 cm; slice thickness, 1.23 mm).
Data were analyzed with Statistical Parametric Mapping 2 (SPM2) running on MATLAB 6.5. MR images were processed using optimized voxel-based morphometry (VBM) in SPM2 as described in detail previously.13, 14 Normalized segmented images were modulated by multiplication with Jacobian determinants of the spatial normalization to encode the deformation field for each subject as tissue density changes in normal space. Following modulation, images were smoothed using a 12 mm full-width half-maximum of isotropic Gaussian kernel, because previous studies had proved that this should be a reasonable filter.13, 15, 16 In addition, we confirmed that the results of statistical analyses with three different smoothing filters (6, 8 and 12 mm Gaussian kernels) were essentially the same.
Statistical analyses were performed with SPM2, which implemented a general linear model. A hypothesis-driven regions of interest (ROIs) approach was used to investigate the hippocampus, using an ROI from the Wake Forest University PickAtlas.17 Our hypothesis is that the PACAP genotype related to the risk of developing schizophrenia is associated with hippocampal volume, because PACAP is associated with hippocampal function in rodents, and hippocampal volume is reported to be reduced in schizophrenia. The genotype and diagnostic effects on hippocampal gray matter volume change were assessed statistically using a single-subject condition and covariate model with a significance level set to 0.05 (corrected for multiple comparisons within the ROI). Age and gender were included in the model to control for confounds. Anatomic localization was according to both MNI coordinates and Talairach coordinates, obtained from M. Brett's transformations (http://www.mrccbu.cam.ac.uk/Imaging/Common/mnispace.shtml) and presented as Talairach coordinates.
Several memory tests, subscales of the Wechsler Memory Scale revised version (logical memory I, logical memory II, visual reproduction I, visual reproduction II, verbal paired associates I (VPAI), verbal paired associates II, visual paired associates I and visual paired associates II) and the general intelligence IQ (from full scale of the Wechsler Adult Intelligence Scale, revised edition, WAIS-R), were performed by some of the subjects recruited at National Center of Neurology and Psychiatry. In association analysis between SNP3 of the PACAP gene and VPAI, group comparisons of demographic data were performed by using unpaired t-tests or χ2, as appropriate. There were no differences between genotype groups and demographic variables, for example, age, gender, education years and full-scale IQ, except for gender distribution in patients with schizophrenia (P=0.026) (Figure 1b). The effects of the SNP3 genotype of the PACAP gene and diagnosis on scores of memory tests were analyzed by a two-way analysis of covariance (ANCOVA), with age, gender and education years as covariates using SPSS 11.0J for Windows (SPSS Japan Inc., Tokyo, Japan). When genotype effects on VPAI in controls or patients with schizophrenia were examined separately, a Mann–Whitney U-test and ANCOVA with gender as a covariate were used.
All animal experiments were carried out in accordance with protocols approved by the Animal Research Committee of Osaka University and by the Ethics Review Committee for Animal Experimentation of the National Institute of Neuroscience. Generation of PACAP−/− mice by a gene targeting technique has been reported previously.7 The null mutation was backcrossed onto the genetic background of Crlj:CD1 (Institute of Cancer Research) mice purchased from Charles River (Tokyo, Japan). All wild-type control mice and PACAP−/− mice (homozygous for the mutant PACAP gene) used in locomotor activity and PPI experiments were obtained from the intercross of heterozygous animals. C57BL/6J mice were purchased from Charles River and were allowed to acclimate in our animal facility for at least 5 days before initiation of experiments. Mice were housed in a temperature- (23±1°C) and light-controlled room with a 12 h light–dark cycle (lights on from 0800 to 2000) and allowed free access to water and food, except during behavioral testing.
Locomotor activity was quantified using an infrared photocell beam detection system, Acti-Track (Panlab, Barcelona, Spain). Following intraperitoneal injection of risperidone (0.1 mg/kg) or an equivalent amount of saline, mice were placed in plastic activity monitoring boxes (30 × 30 × 30 cm) and tracked for 60 min, with data being stored permanently; parameters indicative of locomotor activity, such as distance traveled, were assessed. Each mouse was tested individually and had no contact with the other mice. The PACAP mutant cohort used in locomotor activity testing consisted of 12 wild-type mice and 12 PACAP−/− mice (n=6 each for saline control and risperidone groups).
Acoustic startle responses for PPI were measured in a startle chamber (SR-LAB; San Diego Instruments, CA, USA) as described.18 Mice were placed in the startle chamber for 30 min after intraperitoneal injection of risperidone (0.1 mg/kg) or an equal amount of saline. The testing session started with 5 min of acclimatization to the startle chamber in the presence of 65 dB background broadband (white) noise. Testing consisted of forty 120 dB pulses alone and 10 pulses preceded (100 ms) by a prepulse of 66, 68, 71 or 77 dB. Pulses were randomly presented with an average of 15 s between pulses. Twelve no-stimulus trials were included to assess spontaneous activity during testing. PPI was calculated as a percentage score: PPI (%)=(1−((startle response for pulse with prepulse)/(startle response for pulse alone))) × 100. The PACAP mutant cohort used in PPI testing consisted of 35 wild-type mice (saline control group=22; risperidone group=13) and 33 PACAP−/− mice (saline control group=17; risperidone group=16).
Male C57BL/6J mice weighing 20–25 g received once-daily injections intraperitoneally for 14 days with phencyclidine (PCP) (5 mg/kg; n=13) or saline for control (n=12). PACAP and PAC1 mRNA levels were measured by a real-time quantitative RT–PCR method (TaqMan assay, Applied Biosystems, Tokyo, Japan), using total RNA extracted from the frontal cortex or hippocampus of mice treated with PCP or saline, as described previously.19 Statistically significant differences were assessed by the Mann–Whitney U-test.
We examined the possible association between schizophrenia and genetic variations in the PACAP gene. Seven SNPs in the PACAP gene, selected from public databases, were genotyped, and the genotype distributions of all seven SNPs in the PACAP gene were in Hardy–Weinberg equilibrium in both controls and patients with schizophrenia (data not shown). The allele frequencies of the seven SNPs in patients and controls are shown in Table 1. The major allele of SNP3 and the minor allele of SNP5 were in excess in patients with schizophrenia when compared to controls (SNP3: χ2=7.6, P=0.0059, odds ratio=0.74, 95% confidence interval (CI) 0.59–0.92; SNP5: χ2=4.2, P=0.041, odds ratio=1.38, 95% CI 1.01–1.84), whereas no significant association of the other five SNPs with schizophrenia was observed (Table 1). SNP3 was significantly associated with schizophrenia after Bonferroni correction (corrected P=0.041). We next examined the possible association between schizophrenia and genes encoding the receptors for PACAP, such as the PAC1, VPAC1 and VPAC2 receptor genes. The genotype distributions of all three SNPs in the PAC1, VPAC1 and VPAC2 genes were in Hardy–Weinberg equilibrium in both controls and patients with schizophrenia, except for that of SNP3 of the VPAC1 gene in controls (data not shown). The allele frequencies of the three SNPs in each receptor gene in the patients and controls are shown in Table 2. There was significant evidence for an association between a genetic variant of the PAC1 gene and schizophrenia (SNP2: χ2=6.0, P=0.014, odds ratio=1.18, 95% CI 1.03–1.35, corrected P=0.042), whereas none of the SNPs in the genes encoding VPAC1 or VPAC2 was associated with schizophrenia (Table 2). The evidence that the genes encoding PACAP and its receptor PAC1 are associated with schizophrenia suggests that signaling through PACAP and PAC1 might be associated with the pathophysiology of schizophrenia.
As the PACAP gene has been reported to play a role in learning and memory and hippocampal long-term potentiation in rodents,20, 21 we next examined the possible impact of SNP3 of the PACAP gene, which was associated with schizophrenia, on hippocampal volume in patients with schizophrenia and controls. A genotype effect was found as bilateral reductions of hippocampal volumes (right: P=0.04, t=3.2; left: P=0.002, t=4.1) in homozygous G subjects compared with A-carriers (Figure 1a). There was also a diagnostic effect, a significant reduction in left hippocampal volume in patients with schizophrenia compared with controls (P=0.033, t=3.3). Genotype–diagnosis interaction effects on brain morphology were not found, even at a lenient threshold (uncorrected P=0.05). We next estimated the effects of genotypes on hippocampal volume in the control groups and schizophrenic groups, separately. Schizophrenic patients homozygous for the G allele showed a significant reduction in bilateral hippocampal volumes (right: P=0.013, t=3.5; left: P=0.005, t=3.9). On the other hand, we found significantly decreased volumes of the bilateral hippocampi in homozygous G subjects compared with the A-carriers, at a lenient threshold (uncorrected P=0.05) in controls; however, no voxels could survive after the correction for multiple comparisons. These data suggest that SNP3 in the PACAP gene could have an impact on hippocampal morphology.
As the human hippocampus is related to memory function, we also examined the association between SNP3 of the PACAP gene and several subscales of the Wechsler memory scale revised version in patients with schizophrenia and controls (Figure 1b). Two-way ANCOVA on VPAI revealed significant effects of diagnosis (F=33.8, P<0.0001) and genotype of SNP3 (F=5.2, P=0.024), and an interaction between diagnosis and genotype (F=6.6, P=0.011), whereas an effect of genotype was not found in other memory subscales (data not shown). Individuals homozygous for the G allele of SNP3, which was enriched in schizophrenia, had lower scores of VPAI than schizophrenic patients carrying the A allele (Mann–Whitney U-test: P=0.015); however, there was no difference between the two genotypes in the control group (P>0.8). ANCOVA with gender as a covariate did not alter the statistical significance of these results in patients with schizophrenia (P=0.029). These data suggest that the risk SNP of the PACAP gene could be associated with reduced hippocampal volume and poorer memory performance, which are neurobiological traits related to risk for schizophrenia.
As our data indicate that PACAP might be associated with schizophrenia, PACAP knockout mice (PACAP−/− mice) could be a possible animal model for schizophrenia. Several schizophrenia-related behaviors in rodents, such as hyperactivity, deficits in PPI, locomotor response to antipsychotics, disturbance in social interaction and cognitive deficits, have been commonly observed in previous pharmacological and genetic animal models for schizophrenia.22 Therefore, we examined the impact of an atypical antipsychotic, risperidone, on hyperactivity and deficits in PPI in PACAP−/− mice. PACAP−/− mice maintained high initial levels of locomotor activity during the open field test (Figure 2a and b), as reported previously.7 When treated with risperidone, hyperlocomotion in PACAP−/− mice was attenuated almost to the normal levels seen in wild-type mice; however, treatment with risperidone had no significant effect on locomotor activity in wild-type mice (Figure 2a and b). Risperidone also reversed the diminished PPI in PACAP−/− mice8 to the control level seen in wild-type mice (Figure 2c). Risperidone had no significant effect on PPI levels in wild-type mice (Figure 2c) and startle amplitudes in both PACAP−/− and wild-type mice (data not shown). These results suggest that the abnormal behaviors in PACAP−/− mice, which are believed to be schizophrenia-like phenotypes in rodents, can be rescued by an atypical antipsychotic, risperidone.
The abuse of PCP, an N-methyl-D-aspartic acid receptor antagonist, results in positive symptoms, negative symptoms and cognitive impairments, similar to those seen in patients with schizophrenia. Thus, mice chronically treated with PCP have been used as a potential animal model for schizophrenia.23 To assess a possible change in the expression of PACAP and PAC1 receptor in the pathological state, we performed mRNA expression analysis for PACAP and PAC1 in the frontal cortex and hippocampus of mice chronically treated with PCP. The expression level of PACAP mRNA was significantly reduced in the frontal cortex, but not in the hippocampus (Supplementary Figure 1). On the other hand, increased expression of PAC1 mRNA was observed in both frontal cortex and hippocampus (Supplementary Figure 1). Although the altered expression of PACAP and PAC1 in mouse brains treated with PCP was subtle, these data are considered to be in line with the behavioral abnormalities in PACAP−/− mice, a possible animal model for schizophrenia.
These results using animal models support the notion that PACAP is associated with the pathophysiology of schizophrenia.
Our findings support the possibility that PACAP is a potential schizophrenia susceptibility gene. Clinical association between schizophrenia and the genes encoding PACAP and PAC1 and an association between intermediate phenotypes, hippocampal volume and visual associate memory performance and a risk SNP in the PACAP gene have been demonstrated in our study. There are several limitations in our results. We screened control subjects with no past or current visits to psychiatric services; however, we could not exclude the possibility that they have an undiagnosed or untreated psychiatric disorder. The obtained evidence for association was not very strong, especially in the association between the genotype and visual associate memory performance (P<0.05 level). When we applied corrections for multiple testing for several memory tests, this positive association became negative. This association is not conclusive, although the association between the risk allele for schizophrenia and poorer memory performance might be attractive. Thus, replication studies should be conducted to confirm our findings. We do not know whether SNP3 alters the expression/function of the PACAP gene. Accordingly, there remains the possibility that other polymorphisms, which are in linkage disequilibrium to this polymorphism, are truly responsible for giving susceptibility.
Studies aiming to identify susceptibility genes for schizophrenia are faced with the confounds of subjective clinical criteria and the likelihood of allelic and locus heterogeneity. Although schizophrenia is substantially heritable, the mode of inheritance is complex, involving numerous genes of small effect and a nontrivial environmental component. The concept of intermediate phenotype (endophenotype) assumes that neurobiological deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients and clinically unaffected relatives of schizophrenia patients. The intermediate phenotype approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly inherited traits. Using this approach, we showed an association between the PACAP gene and two intermediate phenotypes, hippocampal volume and visual associate memory, in addition to the genetic association with schizophrenia. Our study could be a successful example of using this strategy to find susceptibility genes for complex diseases.
The hyperactivity and deficits in PPI observed in PACAP−/− mice7, 8 are believed to be schizophrenia-like behaviors in rodents. PAC1 knockout mice also show abnormal behaviors, including elevated locomotor activity and abnormal social behavior.24, 25 Our genetic findings, which demonstrate an association between schizophrenia and two genes, PACAP and PAC1, are supported by the abnormal behaviors in knockout mice of PACAP and PAC1. Risperidone, an atypical antipsychotic, has the advantage of better extrapyramidal tolerability than conventional antipsychotics, but also has advantages in cognitive disturbances and the treatment of negative and depressive symptoms.26 Our previous study showed that haloperidol, a representative conventional antipsychotic, rescued hyperactivity,7 but did not rescue deficits in PPI.8 As risperidone treatment rescued both of these abnormalities in PACAP−/− mice, and as risperidone is a combined D2 and 5-HT2A receptor antagonist, either dopamine or serotonin signaling, or both, could be relevant to the abnormal behaviors in PACAP−/− mice.
Our convergent evidence suggests that investigation of PACAP-PAC1 signaling in the brain could provide a clue to elucidating the possible mechanisms of pathophysiology in schizophrenia.
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We thank Ms Tomoko Shizuno, Keiko Okada and Akiko Murakami for technical assistance and staff of the National Center of Neurology and Psychiatry for recruiting patients and healthy subjects. This work was supported in part by Grants-in-Aid from the Japanese Ministry of Health, Labor and Welfare (H18-kokoro-005, H17-kokoro-001, H17-kokoro-007 and H16-kokoro-002); the Japanese Ministry of Education, Culture, Sports, Science and Technology; Japan Society for the Promotion of Science; CREST (Core Research for Evolutional Science and Technology) of JST (Japan Science and Technology Agency); Japan Foundation for Neuroscience and Mental Health; the Sankyo Foundation of Life Science; and Taisho Pharmaceutical Co Ltd.
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Hashimoto, R., Hashimoto, H., Shintani, N. et al. Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. Mol Psychiatry 12, 1026–1032 (2007) doi:10.1038/sj.mp.4001982
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