Fronto-Striatal Anatomy, Dependent-Behavior, and Neuronal Activity in a Rat Model of Fragile X Syndrome

Background:  Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is considered to be a leading known monogenic cause of autism spectrum disorder and the most common form of inherited mental retardation. FXS is caused by reduced expression in the Fragile X Mental Retardation Protein (FMRP), which is encoded by the FMR1 gene. Patients are left with anatomical abnormalities in their fronto-striatal network, deficits in attention and executive function, which are fronto-striatal-dependent behaviors, and dysfunctional recruitment of this network in an attentional task. Currently no pharmacological treatment for FXS is on the market. There are few robust and replicated morphological, physiological, and behavioral findings from the Fmr1-KO mouse model of FXS, however, therapeutics that successfully reversed negative symptoms in these mice have so far failed to prove efficacy in clinical studies. Potential therapies are more reliable if their therapeutic effects can be replicated in two species before being progressed to clinical trials. Therefore, the field would benefit from a viable rat model. Rats have a more developed prefrontal cortex (PFC), are faster at acquiring complex cognitive tasks that require the PFC, and have larger brains, which facilitate the study of morphology and behavioral electrophysiology.

Objectives:  Studies on the Fmr1-KO rat have the potential to extend observations from existing mouse models on the role of Fmrp in the function of a PFC-related network and provide a better platform for development and evaluation of potential therapeutic strategies. Furthermore, since Fmrp is expressed throughout the brain and a loss of Fmrp may differentially affect brain regions, it is important to study circuits such as the fronto-striatal circuit. This study will aim to test whether insufficiency of Fmrp will cause disruption to the fronto-striatal cognitive network and lead to deficits in its morphology, activity, and dependent behaviors.

Methods: To test the effects of Fmrp loss on fronto-striatal circuit anatomy, this study will compare the regional volumes, dependent behaviors, and electrophysiological function of this circuit between Fmr1-KO rats and wild type (WT) littermates. Volumetric analyses will be conducted using Magnetic Resonance Imaging (MRI). The five-choice serial reaction time task (5-CSRTT), which tests the ability to correctly identify which of five ports has been briefly illuminated, will be used to test attention. Neuronal activity will be examined by recording local field potentials (LFP) of fronto-striatal regions, the PFC, anterior cingulate cortex, and nucleus accumbens, during the behavioral task.

Results: MRI data has been collected and analysis of these images using a pipeline, which performs automated nonbiased brain segmentation, is underway. Fmr1-KO rats display attentional deficits during training on the 5-CSRTT, as evidenced by preliminary data, which show a decrease in accuracy and an increase in omission rate (Figure 1). These deficits suggest that fronto-striatal-associated cognitive behavior is impaired in Fmrp-deficient rats. We are beginning to record LFPs during the 5-CSRTT.

Conclusions:  This multi-level approach will allow for a better understanding of neural mechanisms affected in FXS, with the potential of discovering a new type of treatment target and providing an output measure for screening of potential therapies.