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Study on the role of neuropeptide receptor VPAC2 overactivation in schizophrenia and its potential therapeutic target

陳, 露 大阪大学 DOI:10.18910/87991

2022.03.24

概要

Schizophrenia is a chronic disabling brain disorder affecting approximately 1% of the world's population, and nearly 10% of those with schizophrenia have an affected first-degree relative. Schizophrenia is mainly characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as decreased motivation, and cognitive dysfunction. Approximately one-third of patients with this diagnosis will attempt suicide, and eventually, about only one in ten of these will be successfully treated. New treatments are needed to lessen the suffering of patients and their families and to decrease the economic cost. The advent of the genomic era has led to the discovery of linkages of several genes and pathways to schizophrenia that may serve as new biomarkers or therapeutic targets for this disease. Accumulating evidence indicates that a number of rare copy number variants (CNVs), including both deletions and duplications, have been strongly associated with schizophrenia. Among the most highly penetrant genetic risk factors for neuropsychiatric disorders, clinical studies have shown that microduplications at 7q36.3, containing VIPR2, confer significant risk for schizophrenia. VIPR2 encodes VPAC2, a seven transmembrane heterotrimeric G protein-coupled receptor (GPCR) that binds two homologous neuropeptides with high affinity, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase- activating polypeptide (PACAP). PACAP and its receptors (PAC1, VPAC1, and VPAC2) are expressed in various organs, including the sensory, digestive, and reproductive organs, in addition to the central and peripheral nervous systems, and thus PACAP exhibits a variety of biological activities in a distinct manner. VIP binds to two of the three receptors, VPAC1 and VPAC2, with an affinity similar to that of PACAP. Lymphocytes from patients with 7q36.3 microduplications exhibited higher VIPR2 gene expression and VIP responsiveness (cAMP induction), demonstrating the functional significance of the microduplications. These suggest that overactivation of the VPAC2 receptor signaling is involved in the etiology of schizophrenia and provides large-scale genetic evidence for a specific receptor-mediated (and potentially drug targetable) signaling pathway linked to schizophrenia that is distinct from dopaminergic, glutamatergic, and serotonergic systems. However, the mechanism by which overactive VPAC2 signaling may lead to schizophrenia is unknown. In the present study, to investigate how increased VIPR2 dosage might predispose to psychiatric disorders, we have tried to develop a bacterial artificial chromosome (BAC) transgenic (Tg) mouse model of VIPR2 CNV that recapitulates the genetic architecture of the susceptibility allele. Furthermore, since the VPAC2 receptor is considered an attractive drug target for development to treat schizophrenia, we have tried in another study to develop a selective VPAC2 receptor antagonist peptide.

　BAC is a useful resource for long-range analysis of the genomic organization and gene function. On average, BAC inserts contain 130–200 kb of mouse genomic DNA. Ideally, during BAC transgenesis, BAC DNA introduced by pronuclear injection is integrated as intact BAC molecules into the mouse genome. Tg mice containing intact BAC molecules are likely to show physiologically-relevant gene expression patterns and copy number-dependent expression levels. We generated mice with additional integrated copies of the mouse VIPR2 gene. Potential F0 founder and future progeny were screened by PCR. Southern blot analysis revealed three copies of the transgene in hemizygous F1 generation mice. Lines with documented germlinetransgene transmission were maintained by breeding hemizygous transgenic animals to C57BL/6J wild-type animals. Then, expression of VPAC2 receptor mRNA significantly increased in the prefrontal cortex, cerebral cortex, and hippocampus of VIPR2 BAC Tg mice (F2 generation) compared with wild-type littermates. Interestingly, the expression of PAC1 and VPAC1, but not dopamine-D2, receptor mRNA in the prefrontal cortex of VIPR2 BAC Tg mice was significantly less than that of wild-type mice. VIPR2 BAC Tg mice showed enhanced locomotor activity, disruption in prepulse inibition of the acoustic startle, decrease in social preference, and cognitive impairment. These findings suggest that the VPAC2 receptor link to mental health disorders may be due in part to overactive VPAC2 signaling at a time when neural circuits involved in cognition and social behavior are being established. We have previously found that activation of the VPAC2 receptor impaired axon outgrowth and decreased dendritic arborization in mouse cortical neurons. Thus, alternatively or additionally, VPAC2 overactivity may disrupt ongoing synaptic plasticity during the processes of learning and memory.

　As mentioned above, the VPAC2 receptor might be an attractive drug target for the treatment of schizophrenia because both preclinical and clinical studies have demonstrated a strong link between high expression/overactivation of the VPAC2 receptor and schizophrenia. Despite these backgrounds, the proof- of-concept of VPAC2 inhibitors has not been examined clinically. A reason might be that the VPAC2 receptor belongs to class-B GPCRs, and the discovery of small-molecule drugs against class-B GPCRs is generally difficult. Another issue is the structural properties of the VPAC2 receptor. PACAP also binds tightly to its specific receptor PAC1 and high-affinity receptors for VIP, namely VPAC1 and VPAC2. VPAC1, VPAC2, and PAC1 have moderate amino acid sequence similarities (about 50%) with each other and highly three-dimensional structural homology. VIP selectively activates VPAC1 and VPAC2, and PACAP activates all three receptors. Therefore, these molecular features have made it difficult to discover VPAC2-selective small molecule drugs. Under these circumstances, an artificial 16-mer cyclic peptide VIpep-3, Ac-c(CPPYLPRRLC)TLLLRS-OH, which antagonizes human and rodent VPAC2 signaling pathways in vitro has been reported. In this study, we performed amino acid substitutions and structural optimization of VIpep-3 and obtained its derivative, named KS-133. It was highly stable in rat plasma for at least up to 24 h and showed a VPAC2-selective and potent antagonistic activity. KS-133 had IC50 value of 24.8 nM against VPAC2, which was stronger antagonistic activity than parental VIpep-3 (40.6 nM), even though the molecular weight was reduced from VIpep-3 (1941.1 g/mol) to KS-133 (1558.8 g/mol). KS-133 did not antagonize VIP-VPAC1 and PACAP-PAC1 signaling pathways up to 5 μM. Subcutaneous and intranasal administration of KS-133 suppressed phosphorylation of CREB, a biomarker downstream of the VPAC2 receptor, in the prefrontal cortex of neonatal and adult mice, respectively. We also found that repeated administration of Ro 25-1553, a selective VPAC2 receptor agonist, during postnatal days 1-14 in mice caused cognitive impairment in adulthood and simultaneous treatment with KS-133 prevented this effect. The same postnatally restricted Ro 25-1553 treatment reduced the total branch number and length of apical and basal dendrites of the prefrontal cortex neurons in mice. These morphological abnormalities were counteracted by concomitant administration of KS-133 with Ro 25-1553.

　In conclusion, we successfully generated a BAC Tg mouse model of VIPR2 CNV and developed a novel peptide KS-133 with a potent and selective VPAC2 receptor antagonist activity that counteracts cognitive decline in a mouse model of psychiatric disorders. Our studies would provide a useful mouse model for uncovering the causative pathogenic role of VIPR2 CNV on cognitive circuits and other behavioral manifestations in schizophrenia. KS-133 might contribute to both the development of a novel drug candidate for the treatment of psychiatric disorders such as schizophrenia and the acceleration of fundamental studies on the VPAC2 receptor.

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