DECODE - Cadherin 13 function in the cortico-cerebellar network in neurodevelopmental disorders
Neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), substance use disorder as well as (comorbid) depression, are the largest contributors to disease burden in Europe. They are the leading source of years lost due to disability. Maladaptive cognition and behavior increase the risk for these disorders. Direct and indirect costs associated with these disorders strongly burden the society. Although considerable research efforts go into this field, more work is needed on studying the underlying traits of attention, impulsivity, emotion regulation and social cognition. Recent progress in human genetics has led to the identification of hundreds of genes associated with ASD- and ADHD-like behaviors, including a growing number of genes encoding synaptic proteins. In particular, genetic variations in Cadherin-13 (CDH13) have been implicated in several neurodevelopmental and psychiatric disorders. Recently, rare de novo and inherited deletions at the CDH13 locus have been linked to ASD, indicating the clinical relevance for loss-of-function mutations in CDH13. Previous work from members of DECODE has shown that CDH13 is predominantly expressed at the intersection of where neurons communicate with each other, the synapse. In our DECODE subproject, mouse models will be developed to study the function of CDH13 in specific types of neurons that are thought to be involved in the ASD-related behaviors. In addition, the potential of human induced pluripotent stem cells (iPSCs) will be harnessed to characterize CDH13 dysfunction in patient iPSC-derived cultured neurons. The ultimate aim of the consortium is to understand specific alterations caused by CDH13- deficiency in mouse and human models in order to facilitate designing targeted treatments of these illnesses for precision medicine.
The project is subdivided in the following steps:
- Development of new human and mouse models to elucidate the pathophysiology of CDH13 deficiency. We will generate conditional knockout (cKO) mouse lines by crossing Cdh13loxP/loxP mice with mice expressing CRE recombinase in specific cell types in prefrontal (PFC), dorsal raphe and cerebellum (i.e. SST-Cre, PV-Cre, Ptf1a-CreER, Pet1-Cre). For creating patient-specific cells and to study molecular mechanisms underlying the pathogenesis of neurodevelopmental and psychiatric disorders, induced pluripotent stem cells (iPSCs) from healthy controls and patients carrying genetic variation of CDH13 will be produced and characterized.
- Functional characterization of CDH13 in human cells. IPSCs will be differentiated into bona fide cortical properties of these neurons, super-resolution imaging techniques (e.g. dSTORM), electrophysiological whole-cell patch clamp recordings and live-cell imaging analysis will be conducted.
- Behavioral phenotyping of conditional KO mouse models for CDH13 deficiency. Cdh13 cKO mouse lines will be tested for locomotor activity, impulsivity, sociability and learning deficits.
- Characterization of synaptic and circuitry alterations caused by CDH13 deficiency in mouse models. We will (1) determine the role of CDH13 expressed by cortical SST INs in the formation and localisation of their synapses, cortical excitability and cognition, (2) examine the role of CDH13 in Golgi cell morphology and synaptogenesis, (3) investigate cell-autonomous function of CDH13 in cerebellar Golgi cells, and (4) study whether alteration in serotonergic synapse function affects the excitatory/inhibitory (E/l) balance in cortex and cerebellum.
DECODE aims for a better understanding of the pathogenic mechanisms of a certain group of neurodevelopmental disorders.
We would like to provide our scientific results to the three important groups of interest: the scientific community, benefitting from the knowledge directly; the general public, to integrate our findings into the social frame in general, and, of course, patients and their families, confronted with the burden of a neurodevelopmental disorder.