Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia

Takanori Onouchi,Masafumi Kurosumi,Kazunao Kondo,Takao Senda,Keizo Takao,Chiho Sumi-Ichinose,Atsushi Shimomura,Katsunori Kobayashi,Akiko Iizuka-Kogo,Riccardo Fodde,Ron Smits,Kazuyoshi Sakai,Hidenori Suzuki,Ryuji Nomura,Tsuyoshi Miyakawa,Tetsu Akiyama

doi:10.1186/1756-6606-7-21

Abstract

BackgroundLoss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC is likely to participate in a wide spectrum of biological functions via its different functional domains and is abundantly expressed in the brain as well as in peripheral tissues. However, the neuronal function of APC is poorly understood. To investigate the functional role of Apc in the central nervous system, we analyzed the neurological phenotypes of Apc1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling.ResultsA series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc1638T/1638T mice. Apc1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc1638T/1638T mice showed abnormal dopamine and serotonin distribution in the brain. Some of these behavioral and neuronal phenotypes are related to symptoms and endophenotypes of schizophrenia.ConclusionsOur results demonstrate that the C-terminus of the Apc tumor suppressor plays a critical role in cognitive and neuropsychiatric functioning. This finding suggests a potential functional link between the C-terminus of APC and pathologies of the central nervous system.

Highlights

Loss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis
The total distance traveled by Apc1638T/1638T mice was significantly greater compared with Adenomatous polyposis coli (Apc)+/+ mice (Figure 1A), indicating increased locomotor activity in the Apc1638T/1638T mice
We found a marked reduction in the density and size of dendritic spines in the hippocampal CA1 region of Apc1638T/1638T mice

Summary

Introduction

Loss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC functions as an intracellular regulator of Wnt/ β-catenin signal transduction, which is thought to represent its main tumor suppressing activity [1]. It has been reported that APC is associated with the susceptibility for psychiatric disorders such as depression [6] and schizophrenia [7]. These lines of evidence suggest a potential role for APC in regulating neuronal functions in the brain. Neurological or neuropsychological functions of APC have not been well investigated

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