Investigating Sex Differences in Astrocyte-Mediated Synaptic Development

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Regulation of synaptic connectivity by astrocytes is critical for development of the central nervous system (CNS), yet little is known about how these processes differ between males and females. The long-term goal is to identify mechanisms involved in astrocyte-mediated synaptic development in order to inform novel therapies to prevent or correct disrupted synaptic circuitry in neurodevelopmental diseases in patients of both sexes. The primary objective of this application is to investigate basic fundamental differences in astrocyte-neuron synaptogenic signaling between males and females. The central hypothesis is that thrombospondin (TSP)- induced synaptogenesis is required for proper cortical development of males but less essential for females, establishing sexual dimorphism in astrocyte-mediated synaptic development. The central hypothesis will be tested in three specific aims: 1) Evaluate sex differences in astrocyte synaptogenic signaling; 2) Elucidate the molecular mechanism underlying sex differences in TSP-induced synaptogenesis; and 3) Investigate sex-dependent regulation of dendritic spine and synapse development by the TSP receptor, α2δ-1. In the first aim, astrocyte-conditioned media (containing secreted factors) from either male or female rats will be evaluated for their synaptogenic efficacy on neurons derived from either sex. The impact of astrocytic estrogen receptors as well as neuron-secreted factors on expression and secretion of various astrocytic synaptogenic factors will also be determined. For the second aim, estrogen signaling in TSP- treated cortical neuron cultures will be manipulated to delineate the contributions of brain- derived neurotrophic factor (BDNF), Rac1, and presynaptic muting on astrocyte synaptogenic signaling. In the third aim, male and female in vivo and ex vivo models will be assessed for dendritic spine synaptic development in a transgenic mouse line lacking the TSP synaptogenic receptor, α2δ-1, in the cortex. This research approach is innovative because it will rigorously explore the novel possibility that astrocyte-mediated synaptic development is differentially regulated between males and females and identify estrogen as a prominent regulatory element in this process. The research proposed in this application is significant because it will provide the basis for increasingly robust experimental designs intended to elucidate novel mechanisms of synaptogenesis and astrocyte/neuronal crosstalk in both sexes. Investigating sex differences in astrocyte signaling will expand our understanding of synaptic network formation in both males and females in order to generate innovative strategies to identify, prevent, or correct aberrant synaptic connectivity in developmental CNS disorders such as autism and schizophrenia.