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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    • "In adults, atRA-related functions are confined to a few brain regions such as the hippocampus and subventricular zone (SVZ), where it is involved in the maintenance of adult neurogenesis (Urban et al. 2010; Bonnet et al. 2008) and differentiated state of neurons (Jacobs et al. 2006), regulation of synapse formation, and synaptic plasticity (Aoto et al. 2008; Soden and Chen 2010); however, the mechanism(s) by which it manages these functions is still largely unknown. In the present study, we report that atRA may regulate various neurobiological functions in the adult brain through modulation of region-specific expression of various long noncoding RNAs, which in turn may regulate gene expression patterns. "
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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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    • "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 ) . "

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