We want to investigate the mechanisms responsible for dendritic spine abnormalities in Fragile X syndrome (FXS). FXS is the most common inherited cause of autism and mental retardation. A clear link between the functional and structural (increased density and length of spines) abnormalities in FXS has not been established. A very similar defect in spines has been found in a knockout mouse model of FXS. Spines in FXS resemble dendritic filopodia, which are spine precursors. We show that in developing mouse neocortical neurons, filopodia are replaced by spines in the second postnatal week. Interestingly, the greatest differences in dendritic protrusions between wild type and fragile X mice occur at 1 week of age, and diminish thereafter. It is conceivable that anomalies of filopodia in the first postnatal days are even more striking in the knockout mice, but this has not been explored. Our preliminary data also reveal that dendritic protrusions are longer and more densely packed when neuronal activity is blocked, so it is possible that spontaneous activity is reduced in FXS. Fragile X mice exhibit excessive group I metabotropic glutamate receptor (mGluR)-mediated long-term depression. But a direct link between abnormal mGluR signaling and spine dysgenesis has not yet been discovered. Here, we show that filopodia elongate in response to glutamate and note that others have shown that spines elongate with stimulation of group I mGluRs. We want to test the general hypothesis that a defect in filopodia, linked to abnormal group I mGluR signaling and/or to decreased neuronal activity occurs in FXS, and might impair their ability to mature into spines. Innovative and cutting-edge microscopy techniques will be used. First, we will look for abnormalities of filopodia in pyramidal neurons of fragile X mice with in vivo two-photon imaging in the first postnatal days. Next, we will examine whether spontaneous neuronal activity is reduced in neonatal fragile X mice, using two-photon calcium imaging of hundreds of neurons simultaneously. Finally, we will use two-photon glutamate uncaging to study whether glutamate-mediated elongation of filopodia is disrupted in FXS and whether mGluRs participate in this phenomenon. The experiments in this proposal are designed to identify novel molecular targets for therapeutics in FXS. Because spine abnormalities are common to several other types of mental retardation and autism disorders, these studies are of broad clinical significance.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD054453-04
Application #
7800471
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Urv, Tiina K
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$350,769
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
He, Cynthia X; Cantu, Daniel A; Mantri, Shilpa S et al. (2017) Tactile Defensiveness and Impaired Adaptation of Neuronal Activity in the Fmr1 Knock-Out Mouse Model of Autism. J Neurosci 37:6475-6487
O'Donnell, Cian; Gonçalves, J Tiago; Portera-Cailliau, Carlos et al. (2017) Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders. Elife 6:
O'Donnell, Cian; Gonçalves, J Tiago; Whiteley, Nick et al. (2017) The Population Tracking Model: A Simple, Scalable Statistical Model for Neural Population Data. Neural Comput 29:50-93
Mostany, Ricardo; Miquelajauregui, Amaya; Shtrahman, Matthew et al. (2015) Two-photon excitation microscopy and its applications in neuroscience. Methods Mol Biol 1251:25-42
Contractor, Anis; Klyachko, Vitaly A; Portera-Cailliau, Carlos (2015) Altered Neuronal and Circuit Excitability in Fragile X Syndrome. Neuron 87:699-715
Johnston, David G; Denizet, Marie; Mostany, Ricardo et al. (2013) Chronic in vivo imaging shows no evidence of dendritic plasticity or functional remapping in the contralesional cortex after stroke. Cereb Cortex 23:751-62
He, C X; Portera-Cailliau, C (2013) The trouble with spines in fragile X syndrome: density, maturity and plasticity. Neuroscience 251:120-8
Gonçalves, J Tiago; Anstey, James E; Golshani, Peyman et al. (2013) Circuit level defects in the developing neocortex of Fragile X mice. Nat Neurosci 16:903-9
Cruz-Martín, Alberto; Crespo, Michelle; Portera-Cailliau, Carlos (2012) Glutamate induces the elongation of early dendritic protrusions via mGluRs in wild type mice, but not in fragile X mice. PLoS One 7:e32446
Portera-Cailliau, Carlos (2012) Which comes first in fragile X syndrome, dendritic spine dysgenesis or defects in circuit plasticity? Neuroscientist 18:28-44

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