SECTION Fragile X syndrome (FXS) is the most common inherited form of intellectual impairment and the most common single gene cause of autism. Research in Fmr1 knockout (KO) mice, an animal model of FXS, has identified two major defects in the brain. The first is a structural abnormality in dendritic spines, the major recipients of excitatory synapses in the cortex, and the second is a functional abnormality in synaptic and experience- dependent plasticity. Using in vivo two-photon microscopy, we and others have identified a developmental delay in the stabilization and maturation of dendritic spines of cortical pyramidal neurons in Fmr1 KO mice, which may be one of the earliest synaptic defects in FXS. Now, we will test the hypothesis that circuit remodeling triggered by sensory experience is intimately tied to the spine dynamics and size, thereby reconciling the structural and functional phenotypes of Fmr1 KO mice. We will also investigate synapse integrity at the ultrastructural level with electron microscopy, as well as the dynamics of axons and their boutons during cortical development, in order to ascertain whether they are also altered in mutant mice. In addition, using in vivo two-photon calcium imaging and electrophysiology to record neuronal activity in intact circuits, we have shown that pyramidal neurons in Fmr1 KO mice show abnormally high firing rates and synchrony, which could explain the deficits in learning and low seizure threshold in these mice. Here, we will test the hypothesis that this network hyperexcitability translates into problems with sensory-evoked activity and we will investigate whether these circuit-level problems in KO mice can be rescued with drugs that affect brainstem neuromodulation and inhibitory pathways. The experimental design employs cutting edge in vivo imaging techniques and seeks to address important knowledge gaps and controversial issues in FXS. Because dendritic spine abnormalities and many of the signaling pathways regulated by the fragile X mental retardation protein are also implicated in other neurodevelopmental disorders, we believe that our unique synapse-to- circuit approach has a very high significance and is likely to be of broad importance to many types of autism and mental impairment.
The proposed studies will investigate how brain circuits are assembled during development, how they adapt to sensory experience, and how they are altered in disease states. We will study areas important for emotion, cognition and creativity, as well as for learning and memory. The experiments are designed to generate new ideas about how subtle alterations in brain wiring could result in devastating neuropsychiatric disorders such as autism, mental retardation, and in particular fragile X syndrome.
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