CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBNmutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN–associated ID

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

Exploring attachment to the "homeland" and its association with heritage culture identification

Conceptualisations of attachment to one’s nation of origin reflecting a symbolic caregiver can be found cross-culturally in literature, art, and language. Despite its prevalence, the relationship with one’s nation has not been investigated empirically in terms of an attachment theory framework. Two studies employed an attachment theory approach to investigate the construct validity of symbolic attachment to one’s nation of origin, and its association with acculturation (operationalized as heritage and mainstream culture identification). Results for Study 1 indicated a three-factor structure of nation attachment; the factors were labelled secure-preoccupied, fearful, and dismissive nation attachment. Hierarchical linear modelling was employed to control for differing cultures across participants. Secure-preoccupied nation attachment was a significant predictor of increased heritage culture identification for participants residing in their country of birth, whilst dismissive nation attachment was a significant predictor of decreased heritage culture identification for international migrants. Securepreoccupied nation attachment was also associated with higher levels of subjective-wellbeing. Study 2 further confirmed the validity of the nation attachment construct through confirmatory factor analysis; the three-factor model adequately fit the data. Similar to the results of Study 1, secure-preoccupied nation attachment was associated with increased levels of heritage culture identification and psychological well-being. Implications of the tripartite model of nation attachment for identity and well-being will be discussed

Human intellectual disability genes form conserved functional modules in Drosophila

Contains fulltext : 124936.pdf (publisher's version ) (Open Access)Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules