Fragile X Protein FMRP Is Required for Homeostatic Plasticity and Regulation of Synaptic Strength by Retinoic Acid

Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720-3200, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2010; 30(50):16910-21. DOI: 10.1523/JNEUROSCI.3660-10.2010
Source: PubMed


Homeostatic synaptic plasticity adjusts the strength of synapses during global changes in neural activity, thereby stabilizing the overall activity of neural networks. Suppression of synaptic activity increases synaptic strength by inducing synthesis of retinoic acid (RA), which activates postsynaptic synthesis of AMPA-type glutamate receptors (AMPARs) in dendrites and promotes synaptic insertion of newly synthesized AMPARs. Here, we show that fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates dendritic protein synthesis, is essential for increases in synaptic strength induced by RA or by blockade of neural activity in the mouse hippocampus. Although activity-dependent RA synthesis is maintained in Fmr1 knock-out neurons, RA-dependent dendritic translation of GluR1-type AMPA receptors is impaired. Intriguingly, FMRP is only required for the form of homeostatic plasticity that is dependent on both RA signaling and local protein synthesis. Postsynaptic expression of wild-type or mutant FMRP(I304N) in knock-out neurons reduced the total, surface, and synaptic levels of AMPARs, implying a role for FMRP in regulating AMPAR abundance. Expression of FMRP lacking the RGG box RNA-binding domain had no effect on AMPAR levels. Importantly, postsynaptic expression of wild-type FMRP, but not FMRP(I304N) or FMRPΔRGG, restored synaptic scaling when expressed in knock-out neurons. Together, these findings identify an unanticipated role for FMRP in regulating homeostatic synaptic plasticity downstream of RA. Our results raise the possibility that at least some of the symptoms of fragile X syndrome reflect impaired homeostatic plasticity and impaired RA signaling.

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    • "For example, lack or loss of function mutations in the Rett gene methyl CpG binding protein 2 (MeCP2) disrupt homeostatic network plasticity in the developing cortex (Blackman, Djukic, Nelson, & Turrigiano, 2012). Further, lack of fragile X mental retardation protein (fMRP) disrupts a particular type of homeostatic plasticity in developing hippocampal networks (Soden & Chen, 2010) and may also explain attempted but failed homeostatic responses to disrupted synaptic functioning in the amygdala (Vislay et al., 2013). Disruptions in inhibitory/excitatory balance likely extend to networks like the PFC that are involved in adaptive processes (e.g., Zikopoulos & Barbas, 2013), Thus, considering the degree to which adaptive processes are themselves compromised may be key to understanding variability within groups of individuals with ASD. "
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    ABSTRACT: Resilience and adaptation in the face of early genetic or environmental risk has become a major interest in child psychiatry over recent years. However, we still remain far from an understanding of how developing human brains as a whole adapt to the diffuse and widespread atypical synaptic function that may be characteristic of some common developmental disorders. The first part of this paper discusses four types of whole-brain adaptation in the face of early risk: redundancy, reorganization, niche construction, and adjustment of developmental rate. The second part of the paper applies these adaptation processes specifically to autism. We speculate that key features of autism may be the end result of processes of early brain adaptation, rather than the direct consequences of ongoing neural pathology.
    Development and Psychopathology 05/2015; 27(02):425-442. DOI:10.1017/S0954579415000073 · 4.89 Impact Factor
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    • "How FMRP , which is located near synaptic sites and acts as a translational regulator , affects synaptic scaling is complicated . Using mutant mice in which Fmr1 , the gene that codes for FMRP , had been knocked out , Soden and Chen ( 2010 ) found that FMRP was necessary for the form of synaptic scaling that is mediated by retinoic acid and acts locally through local protein translation ( Aoto et al . , 2008 ) . "

    Homeostatic Control of Brain Function, Edited by Detlev Boison and Susan Masino, 01/2015; Oxford University Press.
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    • "). Both of these developmental disorders have been associated with abnormal retinoic acid signalling (Guris et al. 2006; Soden and Chen 2010). The interrelationship between retinoic acid, its receptors (RARs) and RAI1 are not yet understood. "
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    ABSTRACT: Retinoic acid induced 1 (RAI1) is a protein of uncertain mechanism of action which nevertheless has been the focus of attention because it is a major contributing factor in several human developmental disorders including Smith-Magenis and Potocki-Lupski syndromes. Further, RAI1 may be linked to adult neural disorders with developmental origins such as schizophrenia and autism. The protein has been extensively examined in the rodent but very little is known about its distribution in the human central nervous system. This study demonstrated the presence of RAI1 transcript in multiple regions of the human brain. The cellular expression of RAI1 protein in the human brain was found to be similar to that described in the mouse, with high levels in neurons, but not glia, of the dentate gyrus and cornus ammonis of the hippocampus. In the cerebellum, a second region of high expression, RAI1 was present in Purkinje cells, but not granule cells. RAI1 was also found in neurons of the occipital cortex. The expression of this retinoic acid-induced protein matched well in the hippocampus with expression of the retinoic acid receptors. The subcellular distribution of human neuronal RAI1 indicated its presence in both cytoplasm and nucleus. Overall, human RAI1 protein was found to be a highly expressed neuronal protein whose distribution matches well with its role in cognitive and motor skills.
    Brain Structure and Function 02/2014; 220(2). DOI:10.1007/s00429-014-0712-1 · 5.62 Impact Factor
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