Proper establishment of neuronal circuitry during brain development involves a complex interplay between cellular/molecular processes and neuronal activity that promote the formation of new synapses and elimination of inappropriate synapses. Defects in such processes to control synapse number can result in neurocognitive disorders, including mental retardation and autism spectrum disorders (ASDs). Individuals with autism and a mouse model of Fragile X Syndrome (FXS), the most prevalent inherited form of autism, display increased dendritic spine density in cortical neurons. Many autism-related genes function in regulating proper synapse formation and elimination;therefore, characterizing the cellular mechanisms involved in synapse regulation remains a critical step to understanding autism-spectrum disorders. The transcription factors myocyte enhancer factor 2 (MEF2 A-D) function in developing and adult brains to regulate excitatory synapse elimination in response to neuronal activity. Our lab recently found that MEF2-induced synapse elimination requires the RNA-binding protein, Fragile X Mental Retardation Protein (FMRP), strongly suggesting that deficits in MEF2/FMRP-dependent functional synapse elimination likely contribute to the cortical connectivity abnormalities and behavioral deficits observed in FXS and autism. In preliminary studies using conditional forebrain MEF2 knockout mice, I observe a number of behavioral abnormalities reminiscent of FXS and autism phenotypes in humans. In this NRSA proposal, we outline a series of cutting-edge studies to closely examine the role of MEF2 genes in autism core domain behaviors, and to assess the roles of MEF2 genes and a MEF2 target gene, Arc, in the proper establishment of structural synaptic connectivity in the developing cortex. With synapse elimination defects observed in autism and FXS, we believe that our studies will significantly enhance our understanding of the neurobiology in these complex diseases.
The transcription factor myocyte enhance factor 2 (MEF2) functions in the developing and adult brain to regulate excitatory synapse elimination in response to neuronal activity. Deficits in the cellular processes that control synapse number can result in neurocognitive disorders, including mental retardation and autism spectrum disorders (ASDs). Here, we propose to investigate the developmental requirements of MEF2 in cortical cytoarchitecture and to explore autism-related behaviors in MEF2 conditional knockout animals, a study which will have broad implications for understanding autism, Fragile X Syndrome, and related disorders.
|Harrington, Adam J; Raissi, Aram; Rajkovich, Kacey et al. (2016) MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. Elife 5:|