Glia comprise about half the cells of our nervous system and interact closely with neurons to regulate their shape and functions. While aberrant glia-neuron interactions underlie many diseases, including autism spectrum disorders (ASDs), they remain poorly characterized molecularly. This precludes our understanding of how impaired glia functions contribute to etiology of diseases like ASD.
Glia in many brain regions provide trophic and metabolic support to neurons, in addition to modulating their functions. This, along with the sheer numbers of glia and neurons in nervous systems of many model organisms, makes molecular investigations of glia-neuron interactions challenging. In contrast, there are a defined number of glia and neurons in the genetic model organism C. elegans, which are developmentally invariant across animals. Importantly, C. elegans glia regulate the shape and function of neurons, but not neuron survival. Aakanksha Singhvi’s laboratory aims therefore to exploit C. elegans as a powerful genetic platform to uncover the molecular mechanisms of glia-neuron interactions.
Singhvi’s postdoctoral research previously identified a role for glial KCC-3, a potassium/chloride co-transporter, in regulating sensory-neuron shape and associated animal behavior1. She also discovered that C. elegans glia engulf neuron fragments, reminiscent of mammalian microglia or astrocytes engulfing synaptic endings. Dysregulation of KCC co-transporter function (e.g., KCC2/ SLC12A5) as well as glial engulfment have been implicated in ASD, but their molecular regulation in glia are not well understood.
In this study, Aakanksha Singhvi’s laboratory will dissect how glia molecularly regulate KCC-3 localization and function and the engulfment of neuron fragments. The power, speed and resolution of the C. elegans experimental system has already enabled isolation of mutants with impaired glia-neuron interactions, providing starting tools for this study. Future investigations will be done by combining C. elegans molecular genetic tools with single-cell transcriptomics, cellular imaging, heterologous expression of relevant human ASD risk gene variants in C. elegans and animal behavior studies.
Molecular insights from this work will serve as a framework to understand mechanisms by which dysregulation of glia-neuron interactions implicated in disorders like ASD contribute to sensory and/or cognitive aberrations and neural circuit defects.