Astrocyte transcriptional responses to neuronal activity in the olfactory bulb

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Project Summary/Abstract Astrocytes are non-neuronal cells widely distributed in the brain and astrocyte-neuron communication play critical roles in modulation of behavior. Sensory stimuli like chemical signals of odors activate neurons to induce gene expression changes that facilitate sensory processing. While these are well understood in neurons, whether similar transcriptomic changes also occur in astrocytes are unknown. Here, using in vivo chemogenetic models of neuronal activation, we show astrocytes indeed undergo robust gene expression changes after neuronal activation. A screen through these changes identified a neuromodulator transporter Slc22a3 in olfactory bulb astrocytes. Since preliminary studies revealed odor-evoked neuronal activation also increased astrocytic Slc22a3 in the olfactory bulb, we first asked how Slc22a3 affect astrocyte function in the olfactory bulb? We show that overexpression of astrocyte-specific Slc22a3 led to increased sensitivity to odors implying that astrocytic Slc22a3 affects astrocyte-neuron communication. This leads to the hypothesis that transcriptional activation of astrocytic Slc22a3 is essential for mediating astrocyte-neuron communication during olfactory processing. To test this hypothesis, we propose to use Slc22a3 gain-of-function and loss-of- function mouse models to investigate how astrocytic Slc22a3 affect behaviors and cellular properties of astrocytes (Aim1). Since Slc22a3 transports neuromodulators like serotonin, we next asked how Slc22a3- mediated serotonin transport affect molecular properties of olfactory bulb astrocytes? Since recent studies have shown that serotonin can be directly incorporated into histones to activate transcription, we focused on this epigenetic modification of histone serotonoylation. We show that in olfactory bulb astrocytes, overexpression of Slc22a3 controls histone serotonoylation levels. Therefore, we propose to genetically manipulate astrocytic Slc22a3 expression to determine Slc22a3-mediated histone serotonoylation dynamics in the olfactory bulb (Aim2). Furthermore, preliminary data also revealed that histone serotonoylation levels are increased in astrocytes after odor-evoked neuronal activation. Therefore, using experimental approaches established in Aims1-2, I will directly investigate the function of astrocytic histone serotonoylation in the olfactory bulb (Aim3). Taken together, these results will reveal genetic and epigenetic mechanisms of how astrocytes contribute to olfactory processing. For my career development these studies will provide training in olfactory bulb biology under my mentor Dr. Deneen (expert in astrocyte biology) and co-mentor Dr. Arenkiel (expert in olfactory bulb circuits and behaviors) at Baylor College of Medicine. Since astrocytes are intimately connected with neurons and are dysregulated in all neurological disorders, the broader goal of this proposal is to uncover how astrocytes contribute to healthy processing of the chemical senses of smell. Towards this goal, the proposed research will apply new approaches of astrocyte biology to delineate genetic and epigenetic mechanisms involved in normal function of the smell system.