Does astrocyte dysfunction contribute to synaptic pathologies in autism?

  • Awarded: 2016
  • Award Type: Pilot
  • Award #: 400729

A large number of autism risk genes encode proteins that play critical roles in regulating the formation, maturation and function of synaptic connections in the brain, yet the underlying molecular mechanisms of autism are poorly understood. Synaptic connections in the brain consist of the presynaptic axon, the postsynaptic dendrite and the ensheathing astrocytic process. Astrocytes are morphologically complex, non-neuronal cells that play critical roles in synapse assembly, maturation and function.

Cagla Eroglu and her colleagues aim to assess whether deficits in astrocytic function contribute to the etiology of autism. By cross-referencing high-ranking candidate autism risk genes (scored according to SFARI Gene) to a database of cell-specific gene expression analyses in the murine central nervous system, Eroglu’s group has found that a large number of autism-linked genes are highly expressed and significantly enriched in astrocytes. However, the role of these genes in astrocytes, and how loss of their astrocytic function can contribute to autism, is unknown.

Eroglu hypothesizes that many of these autism risk genes play critical roles in mediating astrocytic regulation of synapse formation and astrocyte-synapse interactions, and that disruption of these genes contributes to autism pathogenesis. To test this hypothesis, Eroglu and colleagues will perform a candidate screen to examine the role of astrocyte-enriched high-ranking autism candidate risk genes in synapse formation, astrocyte morphology and astrocyte-synapse interactions both in vitro and in vivo.

The results of this screen will provide novel insights into the role of astrocyte dysfunction in autism, and will reveal specific molecular mechanisms that facilitate disease pathogenesis. Elucidating the role of these mechanisms in the healthy and diseased brain is of fundamental importance for the development of therapeutic strategies to treat autism.

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