Metabotropic Glutamate Receptor-Mediated Use-Dependent Down-Regulation of Synaptic Excitability Involves the Fragile X Mental Retardation Protein

Department of Biological Sciences, Vanderbilt University, VU Station B, Box 351634, Nashville, TN 37235-1634, USA.
Journal of Neurophysiology (Impact Factor: 2.89). 12/2008; 101(2):672-87. DOI: 10.1152/jn.90953.2008
Source: PubMed


Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.

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    • "The overgrown dendritic arbors in dfmr1 nulls resemble expanded pyramidal cell dendrites found in mouse FXS models and human FXS patients (Comery et al., 1997; Irwin et al., 2000). The correlation between dendritic arbor volume in dfmr1 nulls and neurons experiencing ChR2 depolarization during early-use critical period development suggests excessive excitation in the mutant condition, consistent with established heightened sensory perception (Tessier and Broadie, 2008) and elevated synaptic excitability (Repicky and Broadie, 2009) in the Drosophila FXS model. This connection is also consistent with increased synaptic drive and altered excitation/ inhibition (E/I) synaptic balance in Fmr1 mutant mice (Hays et al., 2011; Patel et al., 2013), as well as increased sensory sensitivity in human FXS patients (Harris et al., 2008). "
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    ABSTRACT: The activity-dependent refinement of neural circuit connectivity during critical periods of brain development is essential for optimized behavioral performance. We hypothesize that this mechanism is defective in fragile X syndrome (FXS), the leading heritable cause of intellectual disability and autism spectrum disorders. Here, we use optogenetic tools in the Drosophila FXS disease model to test activity-dependent dendritogenesis in two extrinsic neurons of the mushroom body (MB) learning and memory brain center: (1) the input projection neuron (PN) innervating Kenyon cells (KCs) in the MB calyx microglomeruli and (2) the output MVP2 neuron innervated by KCs in the MB peduncle. Both input and output neuron classes exhibit distinctive activity-dependent critical period dendritic remodeling. MVP2 arbors expand in Drosophila mutants null for fragile X mental retardation 1 (dfmr1), as well as following channelrhodopsin-driven depolarization during critical period development, but are reduced by halorhodopsin-driven hyperpolarization. Optogenetic manipulation of PNs causes the opposite outcome - reduced dendritic arbors following channelrhodopsin depolarization and expanded arbors following halorhodopsin hyperpolarization during development. Importantly, activity-dependent dendritogenesis in both neuron classes absolutely requires dfmr1 during one developmental window. These results show that dfmr1 acts in a neuron type-specific activity-dependent manner for sculpting dendritic arbors during early-use, critical period development of learning and memory circuitry in the Drosophila brain. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Apr 2015 · Development
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    • "In the case of OD plasticity, Fmr1 KO mice heterozygous for a knockout of mGluR5 (Grm5 +/−), and therefore expressing a 50% reduction in mGluR5 protein, showed the same response as wild-type mice to monocular deprivation [26]. Similar rescues of deficits in spine morphology, increased basal protein synthesis, fear extinction, audiogenic seizures, and learning and memory deficits have been successful [2, 32–34, 36, 37, 39]. However, these experiments, including OD plasticity, focus almost exclusively on alterations in adult animals. "
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    ABSTRACT: Deficits in neuronal plasticity are common hallmarks of many neurodevelopmental disorders. In the case of fragile-X syndrome (FXS), disruption in the function of a single gene, FMR1, results in a variety of neurological consequences directly related to problems with the development, maintenance, and capacity of plastic neuronal networks. In this paper, we discuss current research illustrating the mechanisms underlying plasticity deficits in FXS. These processes include synaptic, cell intrinsic, and homeostatic mechanisms both dependent on and independent of abnormal metabotropic glutamate receptor transmission. We place particular emphasis on how identified deficits may play a role in developmental critical periods to produce neuronal networks with permanently decreased capacity to dynamically respond to changes in activity central to learning, memory, and cognition in patients with FXS. Characterizing early developmental deficits in plasticity is fundamental to develop therapies that not only treat symptoms but also minimize the developmental pathology of the disease.
    Full-text · Article · Jul 2012 · Neural Plasticity
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    • "Numerous studies support the “mGluR theory of FXS” that suggests enhanced group 1 metabotropic glutamate receptor 5 (mGluR5) signaling is responsible for deficits in synaptogenesis, dendritic spine morphology, long-term potentiation (LTP) and depression (LTD) in the disease state [5, 27, 28, 30–32, 34–43]. Consequently, many studies have focused on mGluR inhibitors, such as 2-methyl-6-phenylethynyl-pyridine (MPEP), as a therapeutic intervention for FXS [31, 38–40, 43–47], with considerable success. For example, in the Drosophila disease model, MPEP effectively prevents cellular synaptic deficits and behavioral learning and memory impairments [31, 42, 45, 46]. "
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    ABSTRACT: Fragile X syndrome (FXS) is the most common known genetic form of intellectual disability and autism spectrum disorders. FXS patients suffer a broad range of other neurological symptoms, including hyperactivity, disrupted circadian activity cycles, obsessive-compulsive behavior, and childhood seizures. The high incidence and devastating effects of this disease state make finding effective pharmacological treatments imperative. Recently, reports in both mouse and Drosophila FXS disease models have indicated that the tetracycline derivative minocycline may hold great therapeutic promise for FXS patients. Both models strongly suggest that minocycline acts on the FXS disease state via inhibition of matrix metalloproteinases (MMPs), a class of zinc-dependent extracellular proteases important in tissue remodeling and cell-cell signaling. Recent FXS clinical trials indicate that minocycline may be effective in treating human patients. In this paper, we summarize the recent studies in Drosophila and mouse FXS disease models and human FXS patients, which indicate that minocycline may be an effective FXS therapeutic treatment, and discuss the data forming the basis for the proposed minocycline mechanism of action as an MMP inhibitor.
    Full-text · Article · May 2012 · Neural Plasticity
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