Fragile X syndrome (FXS) is the most common inherited form of an intellectual disability. Children with FXS have been found to have a developmental impairment in the performance of learned skilled limb movements. Motor skill learning is thought to require synaptic plasticity in the primary motor cortex (M1). To better understand how neuronal communication changes with motor learning, it is necessary to determine if learning can induce changes in number, morphology, efficacy, and molecular composition of synapses. FXS results from mutation that causes silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP). Here we will use the fmr1 KO mouse, a murine model for FXS, to study the mechanisms of learning in the primary motor cortex. Our goal is to understand how fmr1 contributes to regulation of synaptic plasticity in the motor cortex and thus elucidate the mechanisms of motor skill learning deficits in the fmr1 KO. We will combine behavioral, electrophysiological, pharmacological, 2-photon imaging and molecular approaches to characterize the changes that occur at synapses in M1 following the learning of a new motor skill in the fmr1 KO mouse. This work is expected to provide important knowledge to develop therapies for FXS and other neurodevelopmental disorders such as autism, a mission of the NIH. !
Fragile X syndrome (FXS) and autism patients have a developmental impairment in the performance of learned skilled limb movements. It is therefore critical to determine the cellular mechanisms that govern motor learning in normal and developmentally abnormal brain. Here we will study the mechanism of motor learning in a mouse model of FXS. This will help to determine the neurobiological basis of the motor skill deficits in FXS and help identify therapeutic targets.
|Bonasera, S J; Chaudoin, T R; Goulding, E H et al. (2017) Decreased home cage movement and oromotor impairments in adult Fmr1-KO mice. Genes Brain Behav 16:564-573|
|Suresh, Anand; Dunaevsky, Anna (2017) Relationship Between Synaptic AMPAR and Spine Dynamics: Impairments in the FXS Mouse. Cereb Cortex 27:4244-4256|
|Suresh, Anand; Dunaevsky, Anna (2015) Preparation of Synaptosomes from the Motor Cortex of Motor Skill Trained Mice. Bio Protoc 5:|
|Padmashri, Ragunathan; Suresh, Anand; Boska, Michael D et al. (2015) Motor-Skill Learning Is Dependent on Astrocytic Activity. Neural Plast 2015:938023|
|Reiner, Benjamin C; Dunaevsky, Anna (2015) Deficit in motor training-induced clustering, but not stabilization, of new dendritic spines in FMR1 knock-out mice. PLoS One 10:e0126572|
|Padmashri, Ragunathan; Reiner, Benjamin C; Suresh, Anand et al. (2013) Altered structural and functional synaptic plasticity with motor skill learning in a mouse model of fragile X syndrome. J Neurosci 33:19715-23|