Protein translation in synaptic plasticity: mGluR-LTD, Fragile X

Abstract

Synaptically activated, rapid and dendritic synthesis of new proteins has long been proposed to mediate long-lasting changes at the synapse [1]. Studies of group 1 metabotropic glutamate receptordependent long-term depression (mGluR-LTD) have provided new insight into dendritic or local translation and plasticity. Here we highlight these exciting results and discuss how synaptic activity controls local translation, the proteins that are synthesized in dendrites, how they affect synaptic function and how altered local translational control contributes to a form of human mental retardation, Fragile X Syndrome. Rapid postsynaptic translation is required for mGluR-dependent LTDPrincipal 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. Empirical data support the role of dendritic protein synthesis in the maintenance of long-term potentiation (LTP) and depression (LTD) [2,3]. Recent advances in our understanding of localized protein synthesis in synaptic plasticity stem from studies of a form of LTD induced by activation of the Gq coupled metabotropic glutamate receptors (mGluR1 and 5; mGluR-LTD). At excitatory synapses onto CA1 pyramidal neurons, LTD can be induced pharmacologically with the group 1 mGluR agonist, DHPG, or by synaptic stimulation of mGluRs via paired-pulse low frequency stimulation of Schaffer collaterals [4, 5]. MGluR-LTD is induced in mature neurons with either paradigm where it requires rapid protein synthesis (~15 minutes) from preexisting mRNA [4,6]. In CA1, mGluR-LTD can be elicited in transected dendrites and affects only active synapses, suggesting that newly required proteins are synthesized in the dendrite and locally weaken synapses [4]. More recently, it was demonstrated that activation of Gq-coupled M1 muscarinic acetylcholine receptors (mAChRs) elicits a protein synthesis dependent LTD that occludes mGluR-LTD in CA1 [7,8]. Therefore, activation of multiple Gq coupled receptors converges upon a single common LTD mechanism that utilizes rapid, postsynaptic protein synthesis. In contrast, another well characterized form

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

“…Multiple lines of evidence strongly support the notion that tight regulation of translational control is critical for the expression of hippocampal mGluR-LTD (Costa-Mattioli et al 2009;Richter and Klann 2009;Waung and Huber 2009). First, translation is required as several general protein synthesis inhibitors block mGluR-LTD (Huber et al 2000).…”

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

“…VNS, if paired with the appropriate regimen of behavioral exposure or cognitive training, may represent a potential intervention to improve these disorders. Plasticity is a core deficit in many postnatal developmental disorders, including autism and forms of mental retardation [106][107][108][109]. Rehabilitative therapies do provide benefits in patients with postnatal developmental disorders.…”

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…The mGlu 1/5 -dependent translational induction of two FMRP targets, Arc/Arg3.1 and MAP1B, which were suggested to be involved in activity-regulated GluA endocytosis in hippocampal neurons (Davidkova and Carroll, 2007;Waung et al, 2008), is absent in Fmr1 KO mice Park et al, 2008). Waung and Huber (2009) thus hypothesized that in the absence of the translational repressor FMRP, several 'LTD-proteins' are already present in excess at the synapse before LTD-inducing stimuli and could contribute to the exaggerated LTD phenotype. This hypothesis is in line with previous studies suggesting increased basal protein expression of MAP1B in the Box 1 FXS, PI3K/mTOR Signaling, and Autism Fragile X syndrome is the most frequent monogenetic form of autism, and evidence is emerging that Fmr1 KO mice represent a suitable animal model to study autism.…”

“…Furthermore, particularly promising groups of FMRPregulated molecules, for example, those involved in AMPA receptor endocytosis (Waung and Huber, 2009), or potassium channels might become candidate therapeutic targets in FXS.…”