Requirement of astrocyte-derived immune signaling for the hippocampal-cortical circuit for social novelty recognition

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ABSTRACT Although the neural mechanisms underlying social behaviors have been extensively studied, the role of glia, such as astrocytes, has been less understood. Astrocytes play crucial roles in postnatal synaptic development and function and contribute to information processing and cognition. Nevertheless, the role of astrocytes in the synaptic refinement of neuronal projections into the medial prefrontal frontal cortex (mPFC), a key area in social behaviors, has been less studied than in other brain regions, such as the thalamus. In the proposed study, we will address the role of astrocytes in social novelty recognition, with a focus on the requirement of astrocyte-enriched cytokine, interleukin-33 (IL-33) for a hippocampal-cortical circuit. IL-33 is a nuclear cytokine abundantly expressed in astrocytes and oligodendrocytes and signals through its receptor, IL1RL1, on microglia and some neurons in the developing and adult brain. We previously reported that mice lacking IL-33 (Il33-/- mice) exhibited social novelty recognition impairment without sociability deficits in the three-chamber social interaction test. Our preliminary data have revealed that IL-33 deletion in astrocytes impairs social novelty recognition and reduces neuronal c-Fos expression in the mPFC, indicating that the neuronal projection from the ventral hippocampus (vHPC) to the mPFC may be attenuated. In addition, microglial alterations are detected in Il33-/- mice during the early postnatal period. Thus, in the proposed study, we will test our hypothesis that astrocyte-microglia IL-33 signaling is required for the postnatal synaptic formation of the vHPC-mPFC projection, contributing to social novelty recognition. In Aim 1, we will evaluate the structural and functional changes of the vHPC-mPFC projection and address its causal role in social novelty recognition deficits in astrocyte-specific IL-33 deficient mice. In Aim 2, we will determine the effects of microglial IL-33 receptor deletion and inducible astrocyte IL-33 deletion on the vHPC-mPFC projection and social novelty recognition to assess the developmental requirement of astrocyte-microglia IL-33 signaling. Together, this exploratory study will assess the role of the vHPC-mPFC projection changes in social novelty recognition deficits in the absence of astrocytic IL-33 and determine the developmental requirement of astrocyte-microglia IL-33 signaling for the maturation of this key neural projection.