The 190 kDa Ankyrin-G isoform is required for the dendritic stability of neurons and its palmitoylation is altered by lithium

Abstract The ANK3 gene, which encodes ankyrin-G (AnkG), is associated with a variety of neuropsychiatric and cognitive disorders including bipolar disorder, autism spectrum disorder, and schizophrenia. These diseases are characterized by abnormal dendritic and synaptic architecture. AnkG is a multifunctional scaffold protein with several isoforms: The 480 kDa and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, but the function of the 190 kDa isoform (AnkG-190) is less well understood. Moreover, AnkG isoforms are regulated by palmitoylation, but palmitoylation of AnkG-190 has not been investigated in neurons. Here we show that AnkG is required for normal dendrite and spine architecture in vivo and that AnkG-190 stabilizes pyramidal neuron dendrites. We found that palmitoylation at Cys70 stabilizes AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Finally, we found that lithium, a commonly used mood stabilizer, reduces AnkG-190 palmitoylation and increases its mobility in spines by inhibiting ZDHHC8 action. Taken together, our data reveal a novel mechanism regulating dendritic architecture and mood stabilizer action on palmitoylation of an important psychiatric disorder risk factor. Significance The ANK3 gene has been associated with bipolar disorder and schizophrenia although the mechanisms of disease are not known. The AnkG 190 kDa isoform, AnkG-190, was previously described for its role in dendritic spines. Here, we show it is required to stabilize dendritic arborization and show that palmitoylation, a post-translation modification which allows proteins to stabilize at the membrane, is critical for its localization. Moreover, we show that lithium, a mood stabilizer commonly used in bipolar disorder, modifies AnkG-190 palmitoylation and its dendritic spine localization by inhibiting ZDHHC8 activity, another protein encoded by a psychiatric disorder risk gene. We describe a new novel function for Ank-190 and the early mechanistic actions of lithium in neurons.