Correlating physiology and transcription during learning in a model for the 22q11.2 deletion

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Project Summary It has been established that episodic memory (EM) encoding is dictated in part by place cell activity and tuning in the CA1 region of the hippocampus. However, it remains largely unknown what the biological mechanisms in place cells are that facilitate this learning capacity. Schizophrenia (SCZ) is a disease that typically arises in early adulthood, affecting roughly 1 in 100 people in the United States alone and exhibit significant cognitive impairments including EM dysfunction. Using calcium imaging to record place cell activity in live behaving mice in a goal-directed learning and memory task it was shown that place cell dynamics in a transgenic mouse model for 22q11.2 deletion syndrome (Df(16)A+/- ), one of the largest known genetic causes of SCZ, are impaired. However, the mechanisms underlying these deficits are still unexplored. The purpose of this proposal is 2 fold: to 1) correlate physiological changes in place cell activity with their transcriptomic changes to better understand the molecular biology underlying place cell tuning in the hippocampus, and 2) to compare changes in the transcriptome in wildtype and Df(16)A+/- mice in vivo to uncover biological processes disrupted in a model for 22q11.2 deletion syndrome during EM encoding. To address this, the following Aims will be performed: Aim 1: Large-scale patch and single cell RNA sequencing of the hippocampal CA1 region in WT mice. Transcriptional, electrophysiological and morphological characterization will be performed on different cell types in the CA1 region including pyramidal, interneuron, and glial cell types. Aim 2: In vivo physiological and correlated transcriptomic profiling in the mouse hippocampal CA1 of WT and Df(16)A+/- mice. I will use genetically encoded calcium indicators (GECIs) delivered by rAAV to correlate hippocampal place cell dysfunction with transcriptomic changes in both WT and mutant mice. scRNAseq will be performed before and after goal-directed learning in WT and Df(16)A+/- mice CA1PCs. Aim 3: Single-cell manipulations to correct altered in vivo physiological properties of CA1 neurons or glia in Df(16)A+/- mice. Using GECIs delivered by rAAV, I will perform in vivo electroporation (IVE) to correct dysregulated genes identified from Aim 2 and restore normal physiological function in Df(16)A+/- mice.