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Behavioral assessment of mice with cell-type specific deletion of FMRP in parvalbumin and somatostatin interneurons

van der Lei, Mathijs (2019) Behavioral assessment of mice with cell-type specific deletion of FMRP in parvalbumin and somatostatin interneurons. Research Project 2, Biomedical Sciences.


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Fragile X syndrome (FXS) is a genetic cause of autism spectrum disorder and intellectual disability. The mutational basis of this disorder is an abnormal trinucleotide CGG repeat expansion in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene, which results in silencing of this gene and lack of transcription and translation of fragile X mental retardation protein (FMRP). Lack of FMRP expression leads to dysregulation of mRNA translation, increased protein synthesis and disturbances in synaptic plasticity. To understand how FMRP contributes to FXS pathophysiology, the Fmr1 knockout (Fmr1 KO) mouse model was generated. Fmr1 KO mice showed alterations in excitatory glutamatergic signaling and inhibitory gamma-aminobutyric acid (GABA) signaling, which may result in an imbalance between excitatory and inhibitory signaling in the brain that underlies autism spectrum disorders. Despite these observations, is the role of FMRP in the GABAergic system less characterized. Alterations in GABAergic inhibitory neurotransmission were found in several brain regions including amygdala, hippocampus and cortex of Fmr1 KO mice. However, the consequence of FMRP deletion in specific GABAergic interneuron subtypes, parvalbumin (PV) and somatostatin (SOM), which are the main inhibitory neurons of the brain, and their specific contribution to behavioral deficits observed in Fmr1 KO mice have never been examined. Therefore, we used Cre/Lox recombinase technology to generate mice with cell type-specific deletion of the FMRP in PV or SOM interneurons (PV-Fmr1-/y and SOM-Fmr1-/y), to assess whether this deletion in specific interneurons results in behavioral impairments that are observed in Fmr1 KO mouse models A battery of behavioral tests for anxiety and repetitive behavior (open field, elevated plus maze, marble burying and self-grooming), locomotor function and learning (rotarod), cognition (novel object recognition, T-maze, Morris water maze and Y-maze) and social interaction (three chamber social interaction test) were performed in this study. Our results demonstrate that SOM-Fmr1-/y mice showed impairments in repetitive behavior (stereotypic counts) and sociability. On the other hand, PV-Fmr1-/y mice showed mild anxiety, impairments in social novelty, spatial memory and cognitive flexibility. Based on these observations, we conclude that deletion of FMRP in specific classes of interneurons results in different types of behavioral phenotypes observed in Fmr1 KO mouse models. Nevertheless, the possible underlying mechanisms remain partly unclear. Although, SOM interneurons are known for their important role in regulating the balance of motor activity and other studies found loss of social preference after specific deletion of FMRP in SOM interneurons. Finally, GABAergic SOM an PV interneurons seem to have different distinct underlying mechanisms that modulate motor activity, social behavior and spatial memory. More research is necessary to investigate the effects of FMRP deletion in specific interneuron classes, whereby future studies with optogenetics and electrophysiological techniques could give more insight in underlying mechanisms.

Item Type: Thesis (Research Project 2)
Supervisor name: Havekes, R.
Degree programme: Biomedical Sciences
Thesis type: Research Project 2
Language: English
Date Deposited: 27 Oct 2019
Last Modified: 28 Oct 2019 10:45

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