Ankyrin-G-190 palmitoylation mediates dendrite and spine morphogenesis and is altered in response to lithium

The ANK3 gene, encoding the protein 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, these 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 Cys70 palmitoylation stabilizes AnkG-190 in spine heads and at dendritic plasma membrane nanodomains, and is necessary for the maintenance of normal spine density, dendrite arborization, and for correct microtubule dynamics. Lithium, a commonly used mood stabilizer, reverses spine and dendrite deficits induced by AnkG knockdown in a manner that is dependent of palmitoylation. Finally, we found that lithium reduces AnkG-190 palmitoylation and increases its mobility in spines. Taken together, our data reveal a novel mechanism regulating dendritic architecture and mood stabilizer action on palmitoylation of an important psychiatric disorder risk factor.