PROJECT: JTC2018: DECODE!

Decrypting Cadherin-13 function in cortico-cerebellar circuitry underlying neurodevelopmental disorders!

Abstract

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social skills and communication, stereotyped and repetitive behavior, and a range of alterations in cognitive function. ASD shows high heritability and comorbidity with other disorders such as intellectual disability and attention-deficit/hyperactivity disorder. The recent progress in human genetics have led to the identification of hundreds of genes associated with autistic-like behaviors, including a growing number of genes encoding synaptic proteins. Recently, rare de novo and inherited deletions at the CDH13 locus have been linked to ASD1,2, indicating the clinical relevance for loss-of-function mutations in CDH13. Although CDH13 has been characterized as an adhesion protein in non-neuronal cells, surprisingly little is known about its function in the brain. In DECODE! we will develop mouse models to study the cell- and circuit-specific effects of CDH13 deficiency. In particular, we will focus on the cortico-cerebellar circuitry, which recently has been implicated in ASD. In addition we will harness the potential of human induced pluripotent stem cells (iPSC) to characterize CDH13 dysfunction in patient iPSC-derived cultured inhibitory neurons at the molecular and cellular level. Understanding circuit-specific alterations caused by CDH13 deficiency in mouse and human models may ultimately help us designing targeted treatment of specific ASD symptoms.

Keywords

autism spectrum disorders, (epi)genetic approaches Stem cells and neural differentiation/cell therapy Behavioural methodologies Electrophisiological approaches Animal studies, GABAergic synapses, CDH13, cortico-cerebellar circuitry

Call topic

Mental Disorders

Proposed runtime

2019 - 2022

Project team

Nael Nadif Kasri (Coordinator)
The Netherlands (NWO)
Klaus-Peter Lesch
Germany (BMBF)
Graziella Di Cristo
Canada (FRQS)
Fabrice Ango
France (ANR)