Subcortical Dendritic Scaffolding in Autism Spectrum Disorder: A Testable ANK2–SCN2A–SHANK Framework

The autism spectrum disorder-associated SCN2A, ANK2, and SHANK-family genes encode molecularly distinct proteins that converge functionally on dendritic integration. Recent work established that ankyrin-B, encoded by ANK2, acts as an obligate dendritic scaffold for NaV1.2, encoded by SCN2A, in neocortical pyramidal neurons. Loss of this module mislocalizes dendritic NaV1.2, reduces dendritic Na+ influx, weakens backpropagating action potentials, and impairs synaptic maturation and long-term potentiation. SHANK proteins organize a complementary postsynaptic receptor scaffold within dendritic spines, coupling N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptor (e.g., mGluR5) signaling to the actin cytoskeleton through layered PSD-95/GKAP/Homer interactions. Disruption of this scaffold can destabilize excitatory transmission, spine morphology, and plasticity. We propose that these dendritic shaft and spine-associated modules jointly regulate dendritic input–output gain and that their disruption may contribute to autism spectrum disorder by destabilizing, rather than uniformly shifting, excitatory integration across cortico-subcortical circuits relevant to sensory reactivity, behavioral flexibility, and social-valence processing. Here, we review the cortical evidence for this layered dendritic convergence and evaluate its potential relevance beyond the cortex. We assess the striatum, thalamus, and amygdala as subcortical sites where related dendritic scaffolding mechanisms may operate. The striatum provides the strongest current test case, with established roles for both NaV1.2 and SHANK3 in medium spiny neuron physiology and corticostriatal connectivity. Thalamic and amygdalar extensions are supported mainly by SHANK-related circuit and channelopathy data but lack direct evidence for ANK2–SCN2A involvement. The framework is experimentally testable: conditional Ank2 deletion in striatal, thalamic, and amygdalar cell types; dendritic Na+/Ca2+ imaging across Scn2a, Ank2, and Shank3 models; adult rescue experiments; and genetic-interaction designs would determine whether ankyrin-B supports dendritic excitability beyond the cortex and whether these genes converge on, rather than merely parallel, dendritic input–output gain. Validation in human subcortical tissue would then establish whether this dendritic scaffolding logic represents a shared point of convergence through which genetically distinct autism spectrum disorder-risk variants alter circuit function.