Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet-like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Abeta40 or Abeta42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.
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PMID:FMRP mediates mGluR5-dependent translation of amyloid precursor protein. 2007 62

Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. However, the functions of mGluRs in the auditory system under normal and diseased states are not well understood. The medial nucleus of the trapezoid body (MNTB) is a critical nucleus in the auditory brainstem nuclei involved in sound localization. In addition to the classical calyx excitatory inputs, MNTB neurons also receive synaptic inhibition and it remains entirely unknown how this inhibition is regulated. Here, using whole-cell voltage clamp in brain slices, we investigated group I mGluR (mGluR I)-mediated modulation of the glycinergic and GABAergic inputs to MNTB neurons in both WT mice and a fragile X syndrome (FXS) mouse model (both sexes) in which the fragile X mental retardation gene 1 is knocked out (Fmr1 KO), causing exaggerated activity of mGluR I and behavioral phenotypes. Activation of mGluR I by (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG) increased the frequency and amplitude of glycinergic spontaneous IPSCs (sIPSCs) in both WT and Fmr1 KO neurons in a voltage-gated sodium channel-dependent fashion, but did not modulate glycinergic evoked IPSCs (eIPSCs). In contrast, 3,5-DHPG did not affect GABAergic sIPSCs, but did suppress eIPSCs in WT neurons via endocannabinoid signaling. In the KO, the effect of 3,5-DHPG on GABAergic eIPSCs was highly variable, which supports the notion of impaired GABAergic signaling in the FXS model. The differential modulation of sIPSC and eIPSC and differential modulation of glycinergic and GABAergic transmission suggest distinct mechanisms responsible for spontaneous and evoked release of inhibitory transmitters and their modulation through the mGluR I signaling pathway.SIGNIFICANCE STATEMENT Neurons communicate with each other through the release of neurotransmitters, which assumes two basic modes, spontaneous and evoked release. These two release modes are believed to function using the same vesicle pool and machinery. Recent works have challenged this dogma, pointing to distinct vesicle release mechanisms underlying the two release modes. Here, we provide the first evidence in the central auditory system supporting this novel concept. We discovered neural-transmitter- and release-mode-specific neuromodulation of inhibitory transmission by metabotropic glutamate receptors and revealed part of the signaling pathways underlying this differential modulation. The results establish the foundation for a multitude of directions to study physiological significance of different release modes in auditory processing.
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PMID:Neurotransmitter- and Release-Mode-Specific Modulation of Inhibitory Transmission by Group I Metabotropic Glutamate Receptors in Central Auditory Neurons of the Mouse. 3009 38