Cortical structures (the hippocampus and neocortex) are critical for cognition and perception, and their improper function is implicated in intellectual disability and autism. The establishment of proper cortical circuits requires a complex interaction of neural activity and genetic programs that control the formation and elimination of specific synaptic connections. Studies of structural excitatory synapses, such as spines, find there is a rapid period of synaptogenesis early in postnatal development followed by a later period of elimination (or pruning) - in both humans and mice. Importantly, sensory experience and circuit activity drives the pruning of spines in vivo. Spine elimination is also triggered by learning in adults and may mediate the refinement of circuits that maintain memories. However, spines are an indirect measure of synaptic number and provide little information about how pruning regulates synaptic function and connectivity of specific cortical pathways. Furthermore, virtually nothing is known of the cellular and molecular mechanisms of activity and sensory experience-dependent synapse elimination in cortical neurons. Using assays of synaptic function in isolated cortical pathways, we have accumulated evidence indicating that activity-dependent synaptic pruning is regulated by the activation of the Myocyte-Enhancer Factor 2 (MEF2) family of transcription factors. We find that the RNA binding protein, Fragile X Mental Retardation Protein (FMRP) is required for MEF2- triggered synapse elimination by regulating the translation of MEF2-generated transcripts - including Protocadherin10 (Pcdh10) and Arc/Arg3.1. We find that Arc and Pcdh10 mediate elimination of synapses through distinct mechanisms. Importantly, loss of function mutations in MEF2C, FMRP and Pcdh10 are linked to intellectual disability (ID), autism and circuit hyperexcitability. Little is known of the physiological and in vivo conditions that lead to elimination of functional synaptic connections on cortical neurons and if or how this involves MEF2c, FMRP, Pcdh10, and Arc.
In Aim 1 we will use optogenetics to induce physiological patterns of CA1 neuron firing and synapse elimination to determine the role of MEF2 isoforms, Fmr1 and Pcdh10 in physiological activity-dependent synapse elimination.
In Aim 2 we will determine if endogenous MEF2 isoforms contribute to developmental pruning of functional excitatory synaptic connections onto cortical neurons in vivo. We also have new data suggesting that a novel experience activates MEF2-dependent Arc transcription which primes CA1 neurons for long-term synaptic depression upon activation of metabotropic glutamate receptors (mGluR-LTD). Novelty-priming of mGluR-LTD may be a precursor to synapse elimination and contribute to the formation of sparse cortical network representations of memories.
In Aim 3 we propose to determine if MEF2 contributes to novelty-induced gene expression, priming of mGluR-LTD, and novelty habituation.
In Aim 4 we will use optogenetics and electrical stimulation to establish an in vitro model of novelty-induced priming of LTD to reveal cellular mechanisms.
Loss of function mutations in the Myocyte-Enhancer Factor 2 (MEF2) family of activity-dependent transcription factors lead to severe mental retardation and autism, but little is known of how MEF2 regulates the brain circuits that underlie cognition, such as cortical neurons. Our data suggest that MEF2 acts in a molecular pathway along with other genes implicated in human cognitive disorders in a synaptic pruning process that is necessary for experience-dependent cortical circuit development and learning. Our proposed experiments will determine the role of MEF2, and other genes linked with cognition, in synaptic pruning during development and learning in mice.
|Zhang, Zilai; Cao, Mou; Chang, Chia-Wei et al. (2016) Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling. Mol Cell Biol 36:70-83|
|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:|
|Byers, Christopher E; Barylko, Barbara; Ross, Justin A et al. (2015) Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1. Biochim Biophys Acta 1850:1310-8|
|Loerwald, Kristofer W; Patel, Ankur B; Huber, Kimberly M et al. (2015) Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development. J Neurophysiol 113:786-95|
|Wilkerson, Julia R; Tsai, Nien-Pei; Maksimova, Marina A et al. (2014) A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Rep 7:1589-600|
|Patel, Ankur B; Loerwald, Kristofer W; Huber, Kimberly M et al. (2014) Postsynaptic FMRP promotes the pruning of cell-to-cell connections among pyramidal neurons in the L5A neocortical network. J Neurosci 34:3413-8|
|Zang, Tong; Maksimova, Marina A; Cowan, Christopher W et al. (2013) Postsynaptic FMRP bidirectionally regulates excitatory synapses as a function of developmental age and MEF2 activity. Mol Cell Neurosci 56:39-49|
|Patel, Ankur B; Hays, Seth A; Bureau, Ingrid et al. (2013) A target cell-specific role for presynaptic Fmr1 in regulating glutamate release onto neocortical fast-spiking inhibitory neurons. J Neurosci 33:2593-604|
|Jakkamsetti, Vikram; Tsai, Nien-Pei; Gross, Christina et al. (2013) Experience-induced Arc/Arg3.1 primes CA1 pyramidal neurons for metabotropic glutamate receptor-dependent long-term synaptic depression. Neuron 80:72-9|
|Niere, Farr; Wilkerson, Julia R; Huber, Kimberly M (2012) Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. J Neurosci 32:5924-36|
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