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Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Structural plasticity of dendritic spines in the nucleus accumbens (NAc) is crucial for learning from aversive experiences. Activation of NMDA receptors (NMDARs) stimulates Ca2+-dependent signaling that leads to changes in the actin cytoskeleton, mediated by the Rho family of GTPases, resulting in postsynaptic remodeling essential for learning. We investigated how phosphorylation events downstream of NMDAR activation drive the changes in synaptic morphology that underlie aversive learning. Large-scale phosphoproteomic analyses of protein kinase targets in mouse striatal/accumbal slices revealed that NMDAR activation resulted in the phosphorylation of 194 proteins, including RhoA regulators such as ARHGEF2 and ARHGAP21. Phosphorylation of ARHGEF2 by the Ca2+-dependent protein kinase CaMKII enhanced its RhoGEF activity, thereby activating RhoA and its downstream effector Rho-associated kinase (ROCK/Rho-kinase). Further phosphoproteomic analysis identified 221 ROCK targets, including the postsynaptic scaffolding protein SHANK3, which is crucial for its interaction with NMDARs and other postsynaptic scaffolding proteins. ROCK-mediated phosphorylation of SHANK3 in the NAc was essential for spine growth and aversive learning. These findings demonstrate that NMDAR activation initiates a phosphorylation cascade crucial for learning and memory. Editor's summary: A component of the strengthened synaptic transmission that occurs in learning and memory is the growth of protrusions on neurons called dendritic spines, which requires activation of the NMDAR family of receptors in the nucleus accumbens. Funahashi et al. delineated the signaling pathway downstream of NMDARs that mediated aversive learning, which enables the identification, prediction, and avoidance of dangerous situations. The authors characterized the proteins phosphorylated in response to NMDAR activation and the kinases responsible. Dendritic spine growth and aversive learning were attenuated when the cytoskeleton-regulating kinase ROCK was pharmacologically inhibited or genetically ablated or when the ROCK-mediated phosphorylation of a specific substrate, the scaffolding protein SHANK3, was blocked in the nucleus accumbens. Thus, the phosphorylation of SHANK3 by ROCK is crucial for the changes in the neuronal actin cytoskeleton that support aversive learning. —Wei Wong [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a relatively common disorder, with a lifetime prevalence of about 1%. Family history is the most important risk factor for schizophrenia, consistent with a genetic contribution to its etiology. Recent human genetic studies reported that some common variants located within BCL9 are associated with schizophrenia in the Chinese population, but not associated with bipolar disorder in the Caucasian population. Methods: Single nucleotide variant (SNP) prioritization sample was comprised of 575 patients with schizophrenia and 564 healthy controls with no personal or family history of psychiatric illness. For SNP association analysis, we used an independent Japanese sample set (replication sample) comprising 1464 cases and 1171 controls. For the analysis of cognitive performance, we investigated 115 cases and 87 controls using Continuous Performance Test (CPT-IP) and the Wisconsin Card Sorting Test Keio version (WCST). Meta-analysis was performed using a combined Japanese total sample (N=3735) and a Chinese sample from a previous study. Results: In the replication sample set, we did not detect any association in 2 SNPs (rs672607 and rs10494252) and schizophrenia. Meta-analysis of rs672607 showed significant association (p-value 0.012, odds ratio 0.855). There was a significant (p

Astrotactin2 (ASTN2) regulates neuronal migration and synaptic strength through the trafficking and degradation of surface proteins. Deletion of ASTN2 in copy number variants has been identified in patients with schizophrenia, bipolar disorder, and autism spectrum disorder in copy number variant (CNV) analysis. Disruption of ASTN2 is a risk factor for these neurodevelopmental disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. However, the importance of ASTN2 in physiological functions remains poorly understood. To elucidate the physiological functions of ASTN2, we investigated whether deficiency of ASTN2 affects cognitive and/or emotional behaviors and neurotransmissions using ASTN2‐deficient mice. Astn2 knockout (KO) mice produced by CRISPR/Cas9 technique showed no obvious differences in physical characteristics and circadian rhythm. Astn2 KO mice showed increased exploratory activity in a novel environment, social behavior and impulsivity, or decreased despair‐, anxiety‐like behaviors and exploratory preference for the novel object. Some behavioral abnormalities, such as increased exploratory activity and impulsivity, or decreased exploratory preference were specifically attenuated by risperidone, but not by haloperidol. While, the both drugs did not affect any emotion‐related behavioral abnormalities in Astn2 KO mice. Dopamine contents were decreased in the striatum, and serotonin or dopamine turnover were increased in the striatum, nucleus accumbens, and amygdala of Astn2 KO mice. In morphological analyses, thinning of neural cell layers in the hippocampus, reduction of neural cell bodies in the prefrontal cortex, and decrease in spine density and PSD95 protein in both tissues were observed in Astn2 KO mice. The present findings suggest that ASTN2 deficiency develops some emotional or cognitive impairments related to monoaminergic dysfunctions and abnormal neuronal morphogenesis with shrinkage of neuronal soma. ASTN2 protein may contribute to the pathogenic mechanism and symptom onset of mental disorders. [ABSTRACT FROM AUTHOR]