Ankyrin-G is a fundamental scaffolding protein that organizes neuronal excitable membrane domains, including the axon initial segment (AIS) and nodes of Ranvier. A new critical role for ankyrin-G was discovered in the formation of GABAergic inhibitory synapses. GABAergic transmission is essential for the proper synchronization and function of neuronal networks that underlie cognition, mood, and behavior. Recent work has shown ankyrin-G also plays a role in excitatory glutamatergic synapses, important for brain function, by regulating dendritic spine morphology, density, and function. Abnormalities in GABAergic interneuron circuitry and dendritic spines have been linked to neuropsychiatric diseases; however, the underlying cellular and molecular mechanisms remain poorly understood. Studies designed in this thesis seek to understand the molecular mechanisms of ankyrin-G at inhibitory GABAergic synapses and excitatory dendritic spines. We generated a knock-in mouse model expressing a W1989R mutation in Ank3, which completely abolishes the ankyrin-G/GABAA receptor-associated protein (GABARAP) interaction to understand how ankyrin-G regulates GABAergic circuity in vivo. Using confocal microscopy and electrophysiological techniques, we show Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapse connectivity and function resulting in pyramidal cell hyperexcitability and disrupted network synchronization. Furthermore, we found changes in pyramidal cell dendritic spines and AISs consistent with compensation for hyperexcitability. We identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Lastly, this thesis explores the role of ankyrin-G in regulating dendritic spines to maintain normal neuronal excitability. This work highlights the importance of ankyrin-G in inhibitory and excitatory synapses and provides novel insights into how ANK3 loss-of-function may contribute to human disease.PHDPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/151713/1/andnels_1.pdfDescription of andnels_1.pdf : Restricted to UM users only.