Browsing by Subject "Fragile X Syndrome"
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Item Multiple Gq-Coupled Receptors Converge on a Common Protein Synthesis-Dependent Long Term Depression That Is Affected in Fragile X Syndrome(2007-12-18) Volk, Lenora Joanne; Huber, Kimberly M.Activation of Gq-coupled group I metabotropic glutamate receptors (mGluR1, mGluR5) induces long-term synaptic depression (LTD) that requires rapid, dendritic protein synthesis. The significance of protein synthesis-dependent mGluR LTD to cognitive function is highlighted by the recent finding that mGluR-dependent LTD is enhanced and protein synthesis-independent in the mouse model of fragile X syndrome mental retardation (FXS, Fmr1 KO mice). In fact, group I mGluR antagonism ameliorates some symptoms of FXS in model organisms. However, disagreement exists in the literature as to the specific roles of mGluR1 and mGluR5 in LTD. Using pharmacological and genetic manipulations, I find that mGluR1 or mGluR5 activation is sufficient to induce LTD. In contrast, I see a selective role for persistent mGluR1 activity in expression of LTD induced with the group I mGluR agonist, DHPG. These data demonstrate a novel role for mGluR1 in induction and expression of LTD at hippocampal Schaffer collateral-CA1 synapses and confirm a role for mGluR5 in induction of LTD at this synapse. LTD induced synaptically with paired-pulse low frequency stimulation (PP-LFS) is Gq- and protein synthesis-dependent and shares common signaling and expression mechanisms with DHPG-induced LTD. However, I find that PP-LFS LTD persists in the presence of group 1 mGluR antagonists and in mGluR1 or mGluR5 knockout mice. These data led to the hypothesis that Gq-coupled receptors other than mGluRs are activated by PP-LFS to induce LTD, and LTD mediated by these receptors should share similar signaling and expression mechanisms with mGluR LTD. A previous study shows that muscarinic acetylcholine receptors (mAChRs) activate protein synthesis in hippocampal CA1 dendrites. Data presented here demonstrate that PP-LFS activates both Gq-coupled mAChRs and mGluRs to induce LTD. Pharmacological activation of mAChRs induces LTD that requires rapid protein synthesis and activation of ERK and mTOR translational activation pathways. New proteins maintain mAChR-dependent LTD through a persistent decrease in surface AMPA receptors. In addition, mAChR LTD is enhanced and protein synthesis-independent in Fmr1 knock-out mice. These data reveal that multiple Gq-coupled receptors converge on a common protein synthesis-dependent LTD mechanism that is aberrant in FXS. These findings suggest novel therapeutic strategies for FXS in the form of mAChR antagonists.Item [News](1982-05-11) Williams, AnnItem The Role of Homer Scaffolding to Metabotropic Glutamate Receptor 5 in the Mouse Models of Neurodevelopement Disorders(2014-04-16) Collins, Katie Anne; Kavalali, Ege T.; Albanesi, Joseph P.; Parada, Luis F.; Huber, Kimberly M.Autism is a neurological disorder characterized by repetetive behaviors, social anxiety and verbal and non-verbal communication. Fragile X Syndrome (FXS) is the most common genetic cause of autism and inheritable form of intellectual disability. FXS is caused by the transcriptional silencing of the Fmr1 gene, which encodes for the Fragile X Mental Retardation Protein (FMRP), which is a Ribonucleic acid (RNA) binding protein. FMRP binds to messenger RNA (mRNA) and suppresses their translation. FMRP regulates hundreds of mRNAs, making it a complex disease with several possible dysfunctions causing the many symptoms, like audiogenic seizures or hypersensitivity. While there are several studies which rescue phenotypes, there is little known about what causes the abnormalities, and if it is possible to replicate the symptoms with a single genetic manipulation. There is also little know about common links between different genetic causes of autism. In this study, I manipulate the interaction between metabotropic glutamate receptor 5 (mGluR5) and Homer, and report how these interactions are important in causing some of the phenotypes in FXS. By rescuing disrupted mGluR5-Homer interactions with a Homer 1a knock out I can rescue several phenotypes, and by disrupting mGluR5-Homer interactions with an mGluR5 knock-in mouse that is mutated so it cannot bind to Homer, I was able to mimic them. I was able to rescue/mimic increased basal translation, altered mGluR-signaling, increased neocortical excitability, decreased anxiety, and partial rescue/mimic audiogenic seizures seen in Fragile X mice. However, I was unable to rescue/mimic the enhanced mGluR-LTD. In this study, I also report how the disrupted mGluR5-Homer interactions are caused by Homer being phosphorylation by CaMKIIα. CaMKIIα is an FMRP target and elevated in the Fmr1 KO mice, causing increased phosphorylation of Homer. Inhibiting CaMKIIα, rescues mGluR5-Homer interactions, basal protein synthesis rates and increased neocortical excitability. Lastly, I report how in PTEN conditional KO (cKO) mice, another autism model, also have disrupted mGluR5-Homer interactions. The PTEN cKO mice have increased neocortical excitability, which can be rescued by inhibiting mGluR5. This suggests a common mGluR5 dysfunction in multiple autism models, which could lead to a common treatment.Item [Southwestern News](2002-04-16) Shields, AmyItem Time bombs in the human genome: exploding triplets that cause disease(1993-03-11) Brown, Michael S.Item Understanding Synaptic and Circuit Disruptions of Excitatory and Inhibitory Function In Fragile X Mental Retardation(2013-04-11) Patel, Ankur 1983-; Huber, Kimberly M.; Gibson, Jay R.; Meeks, Julian P.; Kavalali, Ege T.; Johnson, Jane E.In the mouse model of Fragile X Syndrome, the Fmr1 knockout, local excitation of layer 4 fast-spiking (FS) inhibitory neurons is robustly decreased by 50%, but the mechanisms mediating this change are unknown. Here, I performed recordings in acutely prepared slices obtained from Fmr1 “mosaic” mice where Fmr1 is deleted in about half of all neurons, and I find that loss of presynaptic, but not postsynaptic, Fmr1 fully recapitulates the deficit. The change in connection strength is primarily due to a decrease in multivesicular release and release probability indicating that FMRP normally positively regulates these processes. This change in presynaptic neurotransmitter release is observed both in the mosaic mice and in the constitutive Fmr1 knockout mice. Manipulations in release probability enabled both the mimic and rescue of the impaired function in this synaptic pathway. Loss of presynaptic Fmr1 has no effect on excitatory synapses onto excitatory neurons, indicating a target-cell specific function for presynaptic FMRP. Finally, I demonstrate that the excitation decrement onto FS neurons also exists in layer 5 of the Fmr1 KO suggesting a widespread role for presynaptic Fmr1 in the excitation of inhibitory neurons. In summary, I identify a novel function for presynaptic FMRP in promoting presynaptic neurotransmitter release, and I show that loss of this function accounts for impaired excitation of neocortical FS inhibitory neurons. These changes may contribute to the cognitive dysfunction and circuit hyperexcitability associated with Fragile X Syndrome – including patients with complete deletion of FMRP and those with mosaic expression of FMRP.Item [UT Southwestern Medical Center News](2008-01-08) McKenzie, AlineItem [UT Southwestern Medical Center News](2010-05-11) McKenzie, Aline