Decreased exploratory activity in a mouse model of 15q duplication syndrome; implications for disturbance of serotonin signaling.

Kota Tamada,Fumiyuki Hatanaka,Keizo Takao,Jin Nakatani,Shozo Tomonaga,Tsuyoshi Miyakawa,Toru Takumi,Nobuhiro Nakai,Kazutaka Ikeda

doi:10.1371/journal.pone.0015126

Abstract

Autism spectrum disorders (ASDs) have garnered significant attention as an important grouping of developmental brain disorders. Recent genomic studies have revealed that inherited or de novo copy number variations (CNVs) are significantly involved in the pathophysiology of ASDs. In a previous report from our laboratory, we generated mice with CNVs as a model of ASDs, with a duplicated mouse chromosome 7C that is orthologous to human chromosome 15q11-13. Behavioral analyses revealed paternally duplicated (patDp/+) mice displayed abnormal behaviors resembling the symptoms of ASDs. In the present study, we extended these findings by performing various behavioral tests with C57BL/6J patDp/+ mice, and comprehensively measuring brain monoamine levels with ex vivo high performance liquid chromatography. Compared with wild-type controls, patDp/+ mice exhibited decreased locomotor and exploratory activities in the open field test, Y-maze test, and fear-conditioning test. Furthermore, their decreased activity levels overcame increased appetite induced by 24 hours of food deprivation in the novelty suppressed feeding test. Serotonin levels in several brain regions of adult patDp/+ mice were lower than those of wild-type control, with no concurrent changes in brain levels of dopamine or norepinephrine. Moreover, analysis of monoamines in postnatal developmental stages demonstrated reduced brain levels of serotonin in young patDp/+ mice. These findings suggest that a disrupted brain serotonergic system, especially during postnatal development, may generate the phenotypes of patDp/+ mice.

Highlights

Autism is a widely accepted neurodevelopmental disorder characterized by several major criteria, including impairments in social interaction, verbal and non-verbal communication difficulties, repetitive or rigid behavior, and restricted interest [1]
To determine the free running periods of patDp/+ mice, subjects were initially entrained for 2 weeks to a 12-hour light/dark cycle (LD) and kept in constant darkness condition (DD) for subsequent 2 weeks
Brain levels of NE and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) did not consistently increase or decrease over these developmental stages in patDp/+ mice (Table S2). These results suggest that 5-HT signaling in the brains of patDp/+ mice is altered during these developmental stages. Major autistic phenotypes such as impaired social interaction in the 3-chamber sociability test and perseverative responding in reversal learning tests have been reported in patDp/+ mice from either the C57BL/6J or 129S6 strains [13]

Summary

Introduction

Autism is a widely accepted neurodevelopmental disorder characterized by several major criteria, including impairments in social interaction, verbal and non-verbal communication difficulties, repetitive or rigid behavior, and restricted interest [1]. In several candidate chromosomal regions with relevance for ASDs, duplication of human chromosome 15q11-13 is the most frequent chromosome rearrangement, found in 1–4% of ASDs patients [5] This region is an imprinting region where deletions or methylation abnormalities of paternal and maternal alleles leads to Prader-Willi syndrome and Angelman syndrome, respectively. In chromosomal duplication, these imprinting effects can affect the resulting phenotypes. Recent findings suggest that maternal interstitial duplications may be less prevalent than previously assumed [7], and paternal duplication of this region may lead to autistic-like behavior [7]

Methods

Results

Conclusion