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Master thesis defense: Emilie Mørcholdt Sørensen

Master thesis by Emilie Mørcholdt Sørensen: Autistic behavior in adolescent Fmr1 knockout mice – with parallels to the valproate rat model of autism

2014.11.27 | Henriette Blæsild Vuust

Date Tue 02 Dec
Time 13:00 14:30
Location PET-center meeting room, 6th floor, AUH building 10G, Nørrebrogade 44

Abstract:

Introduction: Autism spectrum disorders (ASDs) represent a group of neurodevelopmental syndromes of social communication impairments and restricted, repetitive patterns of behavior. In 25 % of children with ASD, various associated genetic changes can be identified. Among these, a genetic defect in the FMR1 gene leads to the fragile X syndrome (FXS), the most common form of inherited mental retardation and also known to be strongly related with ASD. The presence and availability of a monogenic mouse model of FXS present a valuable translational tool to unravel the contribution of the FMR1 gene to ASD.

Aim: To study behaviors that are translational relevant to human ASD in the Fmr1 knockout mouse model for FXS and in addition characterize biochemical brain alterations.

Methods: Adolescent Fmr1 knockout and wildtype mice were tested in several behavioral assays with relevance to ASD. Firstly, anxiety and concomitant incidence of locomotor activity were studied in the marble burying test and the open field test. Secondly, recognition memory was studied in the classical novel object recognition task and finally, sociability and social novelty were studied in the tree-chamber test. Serotonergic brain alterations were analyzed by autoradiography to quantify 5-HT2A receptor density in striatal brain slices. Finally in other animals, serotonin and dopamine levels in striatal tissue were measured using HPLC.

Results: Adolescent Fmr1 knockout mice were probably anxious in the open field test, and hyperactivity was clearly evident from both the open field test and the tree-chamber test. In the sociability phase of the three-chamber test, Fmr1 knockout mice showed increased sociability, while in the social novelty phase, Fmr1 knockout mice were not able to discriminate between a familiar and a novel mouse, findings being in contrast to their wildtype littermates. However as a surprise, no statistically significant differences in the biochemical analyses of the serotonergic and dopaminergic systems measured as receptor binding or tissue levels between Fmr1 knockout and wildtype mice were found.

Perspectives: The Fmr1 knockout mouse might be useful to study social behaviors with relevance to ASD when hyperactivity coexists as in ASD clients with ADHD as a comorbidity disorder. Because the etiology of FXS is well characterized, this model could also prove useful in the identification of common pathogenic pathways shared by ASDs. Nevertheless, a continued call for new animal models for ASDs exists to uncover the etiology, for testing new intervention strategies and for the identification of new biomarkers.


Kort resume

Autisme spektrum forstyrrelser (ASF) dækker over en række psykiske lidelser karakteriseret ved sociale og kommunikative forstyrrelser samt stereotyp adfærd. Både arv og miljø har indflydelse på risikoen, og mange gener er involveret udviklingen af ASF. Fragilt X syndrom (FXS) er en lidelse, som skyldes en mutation i ét bestemt gen. Gendefekten er den hyppigste årsag til arvelig mental retardering, og FXS er symptomatisk tæt forbundet med ASF. Man har i en musemodel for FXS efterlignet denne gendefekt, hvilket kan være til gavn i undersøgelsen af gendefektens bidrag til udviklingen af symptomer med relevans for ASF. Formålet med projektet var at undersøge adfærd i FXS musene med relevans for ASF samt at karakterisere biokemiske ændringer i musenes hjerner. Adfærdstestene undersøgte for angstniveau, hyperaktivitet, korttids-hukommelse, social interesse og social præference for nye subjekter. Derudover blev niveauet af forskellige signalstoffer og deres receptorer undersøgt i hjernevæv fra musene. Der var tegn på øget angstniveau i FXS musene, og særligt hyperaktivitet kunne konstateres fra flere af testene. I de sociale tests viste FXS musene modsat forventningen øget interesse for social interaktion, hvilket formentlig var et resultat af hyperaktivitet. FXS musene var ikke mere interesseret i en ny mus i forhold til en velkendt mus, hvilket var i kontrast til kontrolmusene, som udviste social præference for en ny mus. Der kunne endvidere ikke påvises nogle ændringer i de biokemiske målinger. FXS musemodellen kan altså bruges til at undersøge social adfærd med relevans for ASF, men kun i tilfælde hvor hyperaktivitet er tilstede samtidig.


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