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The Journal of Neuroscience, February 4, 2009, 29(5):1514-1524; doi:10.1523/JNEUROSCI.3937-08.2009

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Development/Plasticity/Repair
The FXG: A Presynaptic Fragile X Granule Expressed in a Subset of Developing Brain Circuits

Sean B. Christie,^1 * Michael R. Akins,^1 * James E. Schwob,² and Justin R. Fallon¹

¹Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and ²Department of Anatomy and Cellular Biology, Tufts University Medical School, Boston, Massachusetts 02111

Correspondence should be addressed to Justin R. Fallon, Department of Neuroscience, Brown University, Box G-LN, Providence, RI 02912. Email: Justin_Fallon{at}brown.edu

The loss of Fragile X mental retardation protein (FMRP) causes Fragile X syndrome, the most common inherited mental retardation and single gene cause of autism. Although postsynaptic functions for FMRP are well established, potential roles at the presynaptic apparatus remain largely unexplored. Here, we characterize the expression of FMRP and its homologs, FXR1P and FXR2P, in the developing, mature and regenerating rodent nervous system, with a focus on presynaptic expression. As expected, FMRP is expressed in the somatodendritic domain in virtually all neurons. However, FMRP is also localized in discrete granules (Fragile X granules; FXGs) in a subset of brain regions including frontal cortex, hippocampal area CA3 and olfactory bulb glomeruli. Immunoelectron microscopy shows that FMRP is localized at presynaptic terminals and in axons within these FXG-rich regions. With the exception of the olfactory bulb, FXGs are prominent only in the developing brain. Experiments in regenerating olfactory circuits indicate that peak FXG expression occurs 2–4 weeks after neurogenesis, a period that correlates with synapse formation and refinement. Virtually all FXGs contain FXR2P, while region-selective subsets harbor FMRP and/or FXR1P. Genetic studies show that FXR2P is essential for FXG expression, while FMRP regulates FXG number and developmental profile. These findings suggest that Fragile X proteins play a distinct, presynaptic role during discrete developmental epochs in defined circuits of the mammalian CNS. We propose that the neurological defects in Fragile X syndrome, including the autistic features, could be due in part to the loss of FMRP function in presynaptic compartments.

Key words: Fragile X syndrome; FMRP; FXR2P; olfactory system, axonal regeneration; synaptic plasticity

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Received Aug. 15, 2008; revised Dec. 5, 2008; accepted Dec. 23, 2008.

Correspondence should be addressed to Justin R. Fallon, Department of Neuroscience, Brown University, Box G-LN, Providence, RI 02912. Email: Justin_Fallon{at}brown.edu

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