期刊
NEUROBIOLOGY OF DISEASE
卷 65, 期 -, 页码 142-159出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.01.008
关键词
Fragile X mental retardation protein (FMRP); Mushroom Body; Glutamic acid decarboxylase; Synapse; Calcium signaling; Associative learning
资金
- NIH [R01 MH084989]
Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABA(A) receptor (GABA(A)R) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic alpha/beta Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. latest the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment (C) 2014 Elsevier Inc. All rights reserved.
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