The role of Retinoic Acid Induced 1 (Rai1) in neural network stability

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The brain has the remarkable capacity to be flexible and stable at the same time. This allows us to learn new information while maintaining brain excitability within an operating range. At the cellular level, the brain uses several mechanisms to regulate activity homeostasis, including intrinsic membrane excitability, synaptic transmission, and dendritic morphology. At the network level, the brain uses synaptic scaling to globally normalize synaptic strength. Transcriptional programs have recently emerged as an important player in regulating activity homeostasis. However, how the brain simultaneously controls these processes by transcriptional mechanisms is not fully understood. The long-term objective of my research program is to elucidate the transcriptional mechanism by which the brain maintains homeostatic activity on molecular, cellular, and circuit levels. To achieve this goal, our short-term objective will study how a transcription factor, Retinoic acid induced 1 (Rai1), regulates brain network stability. Neural loss of Rai1 increases brain excitability in mice, suggesting that Rai1 regulates activity homeostasis of the brain. Our preliminary data found a group of excitatory neurons in the hippocampus, the dentate gyrus granule cells (dGCs), are hyperactivated in the absence of Rai1. How Rai1 controls dGCs excitability, morphology, synaptic plasticity, and gene expression is unknown. In this Discovery Research Program, we will use the dGCs as a model to study how Rai1, a transcription factor located in the nucleus, regulates the stability of network activity by coupling intrinsic excitability, homeostatic plasticity, neuronal morphology, and activity-dependent gene expression. This grant will create a new level of understanding of transcriptional mechanisms that control network homeostasis within the brain. Moreover, it will provide excellent conceptual and technical opportunities for trainees to use advanced bioinformatics, morphometric analysis, single cell analysis, and electrophysiology tools while discovering fundamental aspects of brain function and homeostasis.