Fragile X Syndrome (FXS) is the most common, inherited form of intellectual disability and the leading genetic cause of autism 21, 160-164. Transcriptional silencing or loss of function mutations of a single gene, Fmr1, lead to FXS165. Fmr1 encodes a neuronal RNA binding protein, Fragile X Mental Retardation Protein (FMRP) 6. Accumulating evidence indicates that the Gq-coupled metabotropic glutamate receptor 5 (mGluR5) is dysfunctional and overactive in the mouse model of FXS, Fmr1 KO mice 26, 28, 29, 34, 56. Consequently, mGluR5 antagonists reverse many of the phenotypes in FXS animal models and are currently in clinical trials in FXS patients 30, 31, 33-38, 108. The cellular mechanisms of mGluR5 dysfunction in Fragile X have been elusive. A clue comes from the findings that mGluR5 is less associated with the synaptic scaffolding molecule Homer in Fmr1 KO mice 14. The N-terminal EVH1 domain of Homer binds to the C-terminus of mGluR5 as well as signaling effectors, ion channels, and other synaptic scaffolds. The C-terminal coiled-coil domain of Homer dimerizes with other Homer molecules to scaffold mGluR5 to its effectors and the postsynaptic density. A short variant of Homer, Homer1a, lacks the coiled-coil domain, disrupts long Homer scaffolds, which in turn, alters mGluR5 signaling, subcellular localization and causes agonist-independent activity of mGluR5 42, 43, 105, 137, 140, 166, 167. We find that the disrupted mGluR5-Homer interactions mediate much of the altered mGluR5 function as well as the neurophysiological and behavioral phenotypes of Fmr1 KO mice 13, 44. It is unknown if FXS results from a specific disruption in mGluR5-Homer interactions or a disruption of Homer scaffolds in general. To test these ideas, we will determine if Homer interactions with other proteins are affected in Fmr1 KO mice and if a transgenic mouse expressing a knockin mutation of mGluR5 (F1128R) that does not interact with Homer is sufficient to mimic the biochemical, neurophysiological and behavioral phenotypes of Fmr1 KO mice 45. It is unknown what leads to reduced mGluR5-Homer interactions in Fmr1 KO mice. Phosphorylation of mGluR5 20, 46, 47 and Homer at specific sites are known to regulate their interactions .
In Aim 2, we will determine if mGluR5 and Homer phosphorylation are altered in Fmr1 KO mice and examine candidate mechanisms for this altered phosphorylation. FMRP functions to translationally suppress its mRNA targets, which leads to elevated levels of specific proteins in Fmr1 KO mice 6.
In Aim 3, we will determine if elevated levels of a candidate protein in Fmr1 KO mice, known to interact with mGluR5, results in altered mGluR5 function and Homer scaffolds in Fmr1 KO neurons 15, 16.
In Aim 4, we will examine another mouse model of autism to determine if altered mGluR5 function and disrupted mGluR5-Homer scaffolds constitute shared neurobiological mechanisms of autism and FXS 19, 51. Results of this work are expected to determine the core molecular deficits of FXS and autism and provide novel targets for pharmacological intervention.
Excessive mGluR5 activity has been proposed to cause mental retardation and autism associated with Fragile X Syndrome. Here we propose to determine the cellular mechanisms for altered mGluR5 function in Fragile X Syndrome and to determine if altered mGluR5 function is a common cause of autism.
|Guo, Weirui; Molinaro, Gemma; Collins, Katie A et al. (2016) Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice. J Neurosci 36:2131-47|
|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|
|Gross, Christina; Chang, Chia-Wei; Kelly, Seth M et al. (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11:727-36|
|Gross, Christina; Raj, Nisha; Molinaro, Gemma et al. (2015) Selective role of the catalytic PI3K subunit p110Î² in impaired higher order cognition in fragile X syndrome. Cell Rep 11:681-8|
|Fan, Junmei; Zeng, Hongkui; Olson, David P et al. (2015) Vasoactive intestinal polypeptide (VIP)-expressing neurons in the suprachiasmatic nucleus provide sparse GABAergic outputs to local neurons with circadian regulation occurring distal to the opening of postsynaptic GABAA ionotropic receptors. J Neurosci 35:1905-20|
|Guo, Weirui; Ceolin, Laura; Collins, Katie A et al. (2015) Elevated CaMKIIÎ± and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model. Cell Rep 13:2297-311|
|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|
|Smith, Laura N; Jedynak, Jakub P; Fontenot, Miles R et al. (2014) Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration. Neuron 82:645-58|
|Sephton, Chantelle F; Tang, Amy A; Kulkarni, Ashwinikumar et al. (2014) Activity-dependent FUS dysregulation disrupts synaptic homeostasis. Proc Natl Acad Sci U S A 111:E4769-78|
|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|
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