Ankyrin B Promotes Developmental Spine Regulation in the Mouse Prefrontal Cortex

Abstract

AbstractPostnatal regulation of dendritic spine formation and refinement in cortical pyramidal neurons is critical for excitatory/inhibitory balance in neocortical networks. Recent studies have identified a selective spine pruning mechanism in the mouse prefrontal cortex (PFC) mediated by class 3 Semaphorins and the L1-CAM cell adhesion molecules Neuron-glia related CAM (NrCAM), Close Homolog of L1 (CHL1), and L1. L1-CAMs bind Ankyrin B (AnkB), an actin-spectrin adaptor encoded byAnkyrin2(ANK2), a high confidence gene for autism spectrum disorder (ASD). In a new inducible mouse model (Nex1Cre-ERT2:Ank2flox: RCE),Ank2deletion in early postnatal pyramidal neurons increased spine density on apical dendrites in PFC layer 2/3 of homozygous and heterozygousAnk2-deficient mice. In contrast,Ank2deletion in adulthood had no effect on spine density. Sema3F-induced spine pruning was impaired in cortical neuron cultures from AnkB-null mice and was rescued by re-expression of the 220 kDa AnkB isoform but not 440 kDa AnkB. AnkB bound to NrCAM at a cytoplasmic domain motif (FIGQY1231), and mutation to FIGQH inhibited binding, impairing Sema3F-induced spine pruning in neuronal cultures. Identification of a novel function for AnkB in dendritic spine regulation provides insight into cortical circuit development, as well as potential molecular deficiencies in ASD.