Intellectual disabilities (IDs) and autism spectrum disorders link to human APC inactivating gene mutations. However, little is known about adenomatous polyposis coli’s (APC’s) role in the mammalian brain. This study is the first direct test of the impact of APC loss on central synapses, cognition and behavior. Using our newly generated APC conditional knock-out (cKO) mouse, we show that deletion of this single gene in forebrain neurons leads to a multisyndromic neurodevelopmental disorder. APC cKO mice, compared with wild-type littermates, exhibit learning and memory impairments, and autistic-like behaviors (increased repetitive behaviors, reduced social interest). To begin to elucidate neuronal changes caused by APC loss, we focused on the hippocampus, a key brain region for cognitive function. APC cKO mice display increased synaptic spine density, and altered synaptic function (increased frequency of miniature excitatory synaptic currents, modestly enhanced long-term potentiation). In addition, we found excessive β-catenin levels and associated changes in canonical Wnt target gene expression and N-cadherin synaptic adhesion complexes, including reduced levels of presenilin1. Our findings identify some novel functional and molecular changes not observed previously in other genetic mutant mouse models of co-morbid cognitive and autistic-like disabilities. This work thereby has important implications for potential therapeutic targets and the impact of their modulation. We provide new insights into molecular perturbations and cell types that are relevant to human ID and autism. In addition, our data elucidate a novel role for APC in the mammalian brain as a hub that links to and regulates synaptic adhesion and signal transduction pathways critical for normal cognition and behavior.

Intellectual disabilities and autism correlate with human adenomatous polyposis coli (APC) heterozygous gene deletions, but APC's function in the brain is poorly defined. The article by Mohn et al., in this issue, demonstrates that APC conditional knockout (cKO) mice display cognitive impairments and autistic-like behaviors (increased repetitive behaviors, reduced social interest), compared with wild-type (WT) littermates. Additionally, APC loss leads to structural, functional and molecular changes. The micrographs above of hippocampal and cortical pyramidal neuron apical dendrites show the increased spine density and predominance of less-mature stub-shaped spines in APC cKOs, whereas mushroom spines predominate in WTs (Golgi-Cox stained brightfield images, left panels; IMARIS reconstructions of confocal stacks of apical dendrite (red) and spines (blue), right panels). APC cKOs also exhibit excessive β-catenin levels and associated changes in canonical Wnt target gene expression and N-cadherin synaptic adhesion complexes, including reduced levels of presenilin1. The data identify a novel role for APC in linking to and regulating synaptic adhesion complexes and signal transduction pathways that are essential for normal learning and behavior. For more information on this topic, please refer to the article by Mohn et al. on pages 1133-1142.