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. 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.
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|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|
|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|
|Ronesi, Jennifer A; Collins, Katie A; Hays, Seth A et al. (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nat Neurosci 15:431-40, S1|
|Hays, Seth A; Huber, Kimberly M; Gibson, Jay R (2011) Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J Neurosci 31:14223-34|
|Pfeiffer, Brad E; Zang, Tong; Wilkerson, Julia R et al. (2010) Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66:191-7|
|Luscher, Christian; Huber, Kimberly M (2010) Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65:445-59|
|Gibson, Jay R; Huber, Kimberly M; Sudhof, Thomas C (2009) Neuroligin-2 deletion selectively decreases inhibitory synaptic transmission originating from fast-spiking but not from somatostatin-positive interneurons. J Neurosci 29:13883-97|
|Zang, Julie B; Nosyreva, Elena D; Spencer, Corinne M et al. (2009) A mouse model of the human Fragile X syndrome I304N mutation. PLoS Genet 5:e1000758|
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