Protein translation in synaptic plasticity: mGluR-LTD, Fragile X
Section snippets
Rapid postsynaptic translation is required for mGluR-dependent LTD
Principal neurons possess on average 10 000 excitatory synapses. Plasticity of individual or localized regions of synapses is necessary for the information storage capacity of the brain. Upon the discovery of polyribosomes within dendritic shafts and spines, it was suggested that rapid dendritic protein synthesis, triggered by synaptic activity, may serve as a mechanism for long-term plasticity at specific synapses [1]. Empirical data support the role of dendritic protein synthesis in the
mGluR-LTD is altered in the Fragile X Syndrome mouse model
Understanding the mechanisms and function of mGluR-LTD has relevance for human neurological disease because mGluR-LTD is altered in a mouse model of mental retardation and autism, Fragile X Syndrome (FXS). Fragile X Syndrome results from loss of function mutations in Fmr1, which encodes an RNA binding protein, Fragile X mental retardation protein (FMRP) [9]. FMRP associates with dendritic mRNAs and RNA granules, as well as translating polyribosomes, while Fmr1 mRNA is itself present in
Expression mechanisms of mGluR-LTD and candidate ‘LTD proteins’
Determining the molecular mechanisms of mGluR-LTD is essential to understanding how newly synthesized proteins in dendrites mediate plasticity as well as how and why plasticity is altered in Fragile X Syndrome. Activation of mGluRs causes a long-term decrease in surface AMPARs, both GluR1 and GluR2 subunits, lasting for at least an hour [20, 21]. AMPAR endocytosis is required for mGluR-LTD given that postsynaptic injection of D15, a peptide which interferes with dynamin–amphiphysin interactions
Protein synthesis dependent mGluR-LTD in other brain regions
Gq coupled receptor and protein synthesis dependent LTD is observed in multiple brain regions including the neocortex, cerebellum, ventral tegmental area (VTA) and dentate gyrus [8, 30, 31, 32••, 33]. MGluR-LTD has been most well characterized at the cerebellar granule cell-Purkinje cell synapse where strong evidence links LTD to cerebellar dependent learning. Like hippocampal mGluR-LTD, cerebellar mGluR-LTD is mediated by decreases in surface AMPARs and requires new protein synthesis,
mGluR activation of translation initiation
Studies of mGluR-LTD have provided critical knowledge of how synaptic activity activates rapid protein synthesis. Evidence supports the view that mGluRs regulate translation at multiple levels, through regulation of general translation factors as well as RNA binding proteins such as FMRP (Figure 3). MGluR activity stimulates translation initiation through 2 major signaling pathways, the ERK-MAPK and PI3K-mTOR pathways (Figure 3). To initiate translation, mGluRs trigger phosphorylation of
Concluding remarks
The study of mGluR-dependent LTD has provided mechanistic insight into how synaptic activity rapidly activates translation in neurons and in turn, how newly synthesized proteins alter synaptic function. This basic knowledge, in turn guided fruitful experiments into the neuronal function of the mental retardation linked gene Fmr1, the neurobiological deficits in FXS, and the development of novel therapies for the disease [49]. Important questions remain, such as: how are the various
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This research was supported by the grants from the National Institutes of Health NS045711, HD052731, Autism Speaks (KMH), and the UTSW Medical Scientist Training Program T32 GM08014 (MWW).
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The role of altered translation in intellectual disability and epilepsy
2022, Progress in NeurobiologyCorrection of amygdalar dysfunction in a rat model of fragile X syndrome
2021, Cell ReportsCitation Excerpt :Notably, pathway analysis of the fear learning-induced changes in ribosome-bound mRNAs indicates that FMRP is one of the key upstream regulators of axonal protein synthesis in the LA. In the hippocampus, it is well known that DHPG stimulates postsynaptic protein synthesis (Raymond et al., 2000; Weiler and Greenough, 1993), which is disrupted in Fmr1−/y mice (Bowling et al., 2019; Darnell and Klann, 2013; Hou et al., 2006; Osterweil et al., 2010; Waung and Huber, 2009). Thus, it will be important to determine whether fear conditioning-induced presynaptic protein synthesis in the LA requires mGluR5 and whether it is disrupted in Fmr1−/y rats.