Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities

Abstract

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.

Adenomatous Polyposis Coli Protein Deletion in Efferent Olivocochlear Neurons Perturbs Afferent Synaptic Maturation and Reduces the Dynamic Range of Hearing

“…At interneuronal and nerve-muscle synapses, APC organizes a multiprotein synaptic complex that is essential for proper maturation (Wang et al, 2003;Temburni et al, 2004;Rosenberg et al, 2008Rosenberg et al, , 2010Mohn et al, 2014). Blocking APC function in only one of the two synaptic partners at interneuronal nicotinic synapses leads to changes in both presynaptic and postsynaptic specializations, including decreases in nAChR clusters, actively recycling synaptic vesicles, active zone proteins, and neurexin and neuroligin adhesion molecules (Temburni et al, 2004; Rosenberg et al, 2008Rosenberg et al, , 2010.…”

“…APC cKO mice were generated by crossing APC lox468/ lox468 mice (Gounari et al, 2005) with CaMKII-Cre mice (Rios et al, 2001). APC fl/fl Cre-positive mice were used, and APC fl/fl Crenegative littermates served as wild-type (WT) controls (Mohn et al, 2014). CaMKII-Cre ROSA LacZ reporter mice were generated by crossing CaMKII-Cre mice with the ROSA26 Cre reporter strain (Soriano, 1999).…”

“…APC is a ubiquitously expressed scaffold and mRNA binding protein with multiple functions and binding partners (Fearnhead et al, 2001;Preitner et al, 2014). APC loss in neurons leads to excessive ␤-catenin levels and deregulation of both canonical Wntstimulated gene expression and cadherin synaptic adhesion complexes that, in turn, dynamically modulate synaptic density and maturation (Yu and Malenka, 2004;Salinas, 2012;Mohn et al, 2014). Intellectual disabilities and autism are associated with APC heterozygous gene deletions in humans (Heald et al, 2007;Zhou et al, 2007).…”

“…Here, we investigated a role of adenomatous polyposis coli protein (APC) in ribbon synapse differentiation, based on its role in regulating maturation, density, function, and molecular composition of interneuronal synapses (Temburni et al, 2004;Rosenberg et al, 2008Rosenberg et al, , 2010Mohn et al, 2014). APC is a ubiquitously expressed scaffold and mRNA binding protein with multiple functions and binding partners (Fearnhead et al, 2001;Preitner et al, 2014).…”

Knockin’ Out the Spasms

“…The authors have already created conditional APC knock-out (APC cKO) mice in Ca 2+ /calmodulin-dependent protein kinase II-a positive neurons, resulting in loss of control of b-catenin levels. In addition to elevated β-catenin levels in the brain, mice with APC cKO exhibit learning deficits and autismlike behaviors (10). In this study, the mice were investigated using multiple complementary techniques for occurrence of spasms during infancy, seizures during adulthood, EPSCs in Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life.…”