Physical and functional convergence of the autism risk genesScn2aandAnk2in neocortical pyramidal cell dendrites

Abstract

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons, and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. Thus, these results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can be etiological to neurodevelopmental disorder pathophysiology.

Ankyrin-B is lipid-modified by S-palmitoylation to promote dendritic membrane scaffolding of voltage-gated sodium channel NaV1.2 in neurons

“…Given the lack of effect in axonal transport, we asked whether palmitoylation of ankyrin-B could serve other functions. Recently, we showed that ankyrin-B scaffolds the voltage-gated sodium channel Na V 1.2 at the dendritic membrane to promote dendritic excitability and synaptic function ( Nelson et al, 2022 ). Here, we asked whether palmitoylation was required for ankyrin-B to scaffold Na Vdendritic localization due to ankyrin 1.2 at the dendritic membrane.…”

“…Axons were identified both by morphology (as axons are much longer and thinner than dendrites) and by a relative lack of ankyrin-B staining in the proximal axon ( Galiano et al, 2012 ). Residual Na V 1.2-3x FLAG staining in the proximal axon was confirmed to be localized to the AIS by colocalization with the AIS scaffolding protein, ankyrin-G ( Nelson et al, 2022 ).…”

“…In neurons, multiple axonal roles have been shown for ankyrin-B, including axonal cargo transport, scaffolding of cell adhesion molecules to repress axonal branching, and proper positioning of ankyrin-G at the axon initial segment (AIS) ( Galiano et al, 2012 ; Lorenzo et al, 2014 ; Yang et al, 2019 ). By contrast, the role of ankyrin-B at dendritic membranes had been relatively understudied until recently, when ankyrin-B was shown to serve as an essential scaffold for voltage-gated sodium channels, Na V 1.2, at dendrites to promote dendritic excitability and synaptic plasticity in neocortical pyramidal neurons ( Nelson et al, 2022 ). Heterozygous loss of Ank2 causes dramatic impairments in dendritic excitability and synaptic plasticity, and phenocopies effects of heterozygous loss of Scn2a , which encodes Na V 1.2, suggesting ankyrin-B is critical for Na V 1.2-mediated dendritic function ( Spratt et al, 2019 ; Nelson et al, 2022 ).…”

Epilepsy-associatedSCN2A(NaV1.2) Variants Exhibit Diverse and Complex Functional Properties

“…This variant affects a residue in the D2-D3 cytoplasmic domain near an ankyrin binding site. A recent study provided evidence that loss of ankyrin-B scaffolding of Na V 1.2 in cortical neurons phenocopies the neurophysiological defects observed in Scn2a haploinsufficient mice (28). These observations raise the possibility that D1050V disrupts Na V 1.2 interactions with ankyrin and mimics a channel loss-of-function.…”

Ankyrin-B is lipid-modified by S-palmitoylation to promote dendritic membrane scaffolding of voltage-gated sodium channel Nav1.2 in neurons

“…In neurons, multiple axonal roles have been shown for ankyrin-B, including axonal cargo transport, scaffolding of cell adhesion molecules to repress axonal branching, and proper positioning of ankyrin-G at the axon initial segment (AIS) (Galiano et al, 2012;Lorenzo et al, 2014;Yang et al, 2019). By contrast, the role of ankyrin-B at dendritic membranes had been relatively understudied until recently, when ankyrin-B was shown to serve as an essential scaffold for voltage-gated sodium channels, Nav1.2, at dendrites to promote dendritic excitability and synaptic plasticity in neocortical pyramidal neurons (Nelson et al, 2022). Heterozygous loss of Ank2 causes dramatic impairments in dendritic excitability and synaptic plasticity, and phenocopies effects of heterozygous loss of Scn2a , which encodes Nav1.2, suggesting ankyrin-B is critical for Nav1.2-mediated dendritic function (Spratt et al, 2019;Nelson et al, 2022).…”