Using C. elegans to Decipher the Cellular and Molecular Mechanisms Underlying Neurodevelopmental Disorders

Abstract

Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.

The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development

“…The worm motor circuit requires E/I balance for proper function, which makes this model circuit valuable for studying molecular and cellular mechanisms of neurodevelopmental disorders (Bessa et al, 2013). Our results indicate EEL-1 is required for GABAergic presynaptic transmission and E/I balance in the motor circuit.…”

“…Recent studies have begun to explore the molecular mechanisms that regulate E/I balance in the worm motor circuit, which remain poorly understood (Cherra and Jin, 2016; Jospin et al, 2009; Kowalski et al, 2014; Stawicki et al, 2011; Vashlishan et al, 2008). Over the past decade, this simple circuit has also emerged as a valuable tool for understanding the molecular and cellular mechanisms that affect neurodevelopmental disorders, such as epilepsy and autism (Bessa et al, 2013). …”

Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications

“…Among the most used are mouse models, which can be engineered in several ways: some express multiple genes within the human chromosomal region that is being studied; others have the syntenic region deleted or duplicated; finally, there are individual gene knockout or overexpression models which allow us to dissect the contribution of a particular gene to a given phenotype 131 132. Other models, like zebra fish or Caenorhabditis elegans , are also used particularly to assess the function of particular genes 133 134. More recently, the possibility of using human induced pluripotent stem cells (hiPSCs) has opened a wide range of experiment possibilities, including in drug screening 135…”

Worms on the spectrum - C. elegans models in autism research

“…However, disadvantages of using iPSCs include their lack of integration in functional circuits, interaction with other cell types, and absence of A C C E P T E D M A N U S C R I P T 8 behavioural phenotypes (Bessa et al, 2013). Using iPSCs to model ASD have been discussed in more detail elsewhere (Nestor et al, 2016;Wan et al, 2015).…”