TY - JOUR T1 - Longitudinal assessment of Glutamatergic Neurosystem in Fragile X Knock Out Mouse Model JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 118 LP - 118 VL - 62 IS - supplement 1 AU - Sepideh Afshar AU - Xiying Qu AU - Gengyang Yuan AU - Sevda Lule AU - Michael Whalen AU - Anna-Liisa Brownell AU - Maria Mody Y1 - 2021/05/01 UR - http://jnm.snmjournals.org/content/62/supplement_1/118.abstract N2 - 118Introduction: Fragile X syndrome (FXS) is a monogenic developmental disorder caused by mutations of the Fragile X Mental Retardation 1 (FMR1) gene. Patients with FXS are characterized by learning disabilities and cognitive impairments. In the face of failures of clinical trials with FXS, we focused on PET imaging of FMR1 knockout mice and their performance on the Morris Water Maze (MWM) task, a measure of spatial learning and memory, towards developing a biobehavioral marker for FXS. Methods: A cohort of FXS mice and age- and gender-matched healthy control mice underwent longitudinal PET imaging using allosteric modulator compound [18F]FPEB (3-[18F]flouro-5-(2-pyridinylethynyl) to examine mGluR5 expression combined with behavioral performance on the MWM and open field tasks at three time points: when mice were between 34-41 days old (A1), between 156-219 days (A3) and between 325-398 days (A4). An additional PET imaging was conducted at age between 84-100 days (A2). The data were statistically analyzed (t-tests and repeated measure ANOVA) to evaluate the effects of independent variables (age and gender) on the dependent variable (FPEB binding potential, BP in PET analysis) in multiple brain regions. Results: Repeated measure ANOVA (gender and age) of the PET data at each brain area revealed a significant interaction between age and gender at three brain areas, striatum, cortex, and hippocampus (p<0.041) in FXS group as well as main effect of time (p<3.0e-7) in both groups. Further analysis showed that the difference between male and female mice was significant at age group A1 and A4 (p<0.051) in FXS group. In general, females showed lower binding potential than males, and the binding potential reduced with time except a sudden increase at age group A2 in male mice. Furthermore, we observed a significant increase in linear learning rate (p<0.020) from the latency trials on finding the hidden platform in FXS group but no difference in the mean latency. Finally, the ANOVA analysis of distance travelled by the mice in an open field test indicated a significant main effect of age (p=0.005) and significant reduced distance in FXS group from age group A3 to A4 in keeping with lower binding potential at older ages. Conclusion: These findings reflect the critical brain areas known to be impacted by the progression of the FXS syndrome namely, striatum, cortex, and hippocampus. In addition, a biobehavioral vulnerability was predicted on the basis of disease progression and hold exciting potential as targets for pharmacological interventions. Acknowledgement: The research was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program under Award No. W81XWH-17-1-0228 to ALB. ER -