Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and one of the main identified genetic causes of autism spectrum disorder. Astrocytes, a type of glial cells, perform multiple tasks in the brain and have been implicated in regulating synaptic development, function and plasticity. Yet the role astrocytes play in neurodevelopmental disorders is not well understood. In this proposal, we aim to identify the contribution of astroglial Fragile X Mental Retardation Protein (FMRP) to altered astrocyte Ca2+ signaling, synaptic deficits and cortical plasticity impairments associated with FXS. We approach this through three aims which utilize mouse genetics, in vivo imaging of Ca2+ signaling and synaptic protein trafficking, cell and molecular techniques and mouse behavior.
In Aim 1, we will study the role of FMRP in regulating astrocytic Ca2+ signaling. We will perform in vivo imaging of astrocytic Ca2+ signaling in awake fmr1 KO mice and in transgenic mice in which FMRP is selectively deleted or exclusively expressed in astrocytes.
In Aim 2, we will examine mechanisms of altered astrocytic Ca2+ signaling in FXS with cell, molecular and pharmacologic experiments.
In Aim3, we will examine if loss of FMRP in astrocytes results in basal and learning-induced alterations in functional and structural synaptic plasticity by electrophysiology and in vivo imaging of tagged AMPAR trafficking in dendritic spines, in astrocyte-specific FMRP knockout mice. This work is expected to provide important knowledge about the role of astrocytes in FXS and has the potential to identify novel therapeutic targets for FXS.
This research proposal is relevant to public health because it addresses the molecular and cellular mechanisms of Fragile X syndrome (FXS), the most common form of inherited intellectual disability. The goal of this proposal is to investigate role of non-neuronal cells, astrocytes, in the pathogenesis of FXS. We will use methods of in vivo functional and structural cellular imaging, molecular neuroscience, electrophysiology, and animal behavioral analysis.
