scholarly journals The Coordination of Local Translation, Membranous Organelle Trafficking, and Synaptic Plasticity in Neurons

2021 ◽  
Vol 9 ◽  
Author(s):  
Dipen Rajgor ◽  
Theresa M. Welle ◽  
Katharine R. Smith
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Local Translation ◽  
Local Protein Synthesis ◽  
Regulatory Processes ◽  
Regulation Of Activity ◽  
Activity Dependent

Neurons are highly complex polarized cells, displaying an extraordinary degree of spatial compartmentalization. At presynaptic and postsynaptic sites, far from the cell body, local protein synthesis is utilized to continually modify the synaptic proteome, enabling rapid changes in protein production to support synaptic function. Synapses undergo diverse forms of plasticity, resulting in long-term, persistent changes in synapse strength, which are paramount for learning, memory, and cognition. It is now well-established that local translation of numerous synaptic proteins is essential for many forms of synaptic plasticity, and much work has gone into deciphering the strategies that neurons use to regulate activity-dependent protein synthesis. Recent studies have pointed to a coordination of the local mRNA translation required for synaptic plasticity and the trafficking of membranous organelles in neurons. This includes the co-trafficking of RNAs to their site of action using endosome/lysosome “transports,” the regulation of activity-dependent translation at synapses, and the role of mitochondria in fueling synaptic translation. Here, we review our current understanding of these mechanisms that impact local translation during synaptic plasticity, providing an overview of these novel and nuanced regulatory processes involving membranous organelles in neurons.

scholarly journals Cortical wiring by synapse-specific control of local protein synthesis

2021 ◽  
Author(s):  
Clémence Bernard ◽  
David Exposito-Alonso ◽  
Martijn Selten ◽  
Stella Sanalidou ◽  
Alicia Hanusz-Godoy ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Synapse Formation ◽  
Mrna Translation ◽  
Protein Translation ◽  
Synaptic Proteins ◽  
Local Synthesis ◽  
Local Protein Synthesis ◽  
Mouse Cerebral Cortex ◽  
A Cell ◽  
Local Protein

Neurons use local protein synthesis as a mechanism to support their morphological complexity, which requires independent control across multiple subcellular compartments including individual synapses. However, to what extent local translation is differentially regulated at the level of specific synaptic connections remains largely unknown. Here, we identify a signaling pathway that regulates the local synthesis of proteins required for the formation of excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves the regulation of the mTORC1 inhibitor Tsc2 by the receptor tyrosine kinase ErbB4, which enables the local control of mRNA translation in a cell type-specific and synapse-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins that regulates the formation of excitatory inputs on PV+ interneurons downstream of ErbB4 signaling. Our work demonstrates that local protein translation is regulated at the level of specific connections to control synapse formation in the nervous system.

Dysregulation of Neuronal Protein Synthesis in Alzheimer’s Disease

2020 ◽  
Author(s):  
Tao Ma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Initiation Factor ◽  
Early Event ◽  
Molecular Signaling

Currently there is no effective cure or intervention available for Alzheimer’s disease (AD), a devastating neurodegenerative disease and the most common form of dementia. It is urgent to understand the basic cellular/molecular signaling mechanisms underlying AD pathophysiology to identify novel therapeutic targets and diagnostic biomarkers. Many studies indicate impaired synaptic function as a key and early event in AD pathogenesis. Mounting evidence suggests that dysregulations in mRNA translation (protein synthesis) may contribute to the development of synaptic dysfunction and cognitive defects in neurodegenerative diseases including AD. Protein synthesis happens in three phases (initiation, elongation, and termination) and is tightly controlled through regulation of multiple signaling pathways in response to various stimuli. Integral protein synthesis is indispensable for memory formation and maintenance of synaptic plasticity. Interruption of protein synthesis homeostasis can lead to impairments in cognition and synaptic plasticity. This chapter reviews recent studies supporting the idea that impaired protein synthesis is an important mechanism underlying AD-associated cognitive deficits and synaptic failure. It focuses on three signaling cascades controlling protein synthesis: eukaryotic initiation factor 2α (eIF2α), the mammalian target of rapamycin complex 1 (mTORC1), and eukaryotic elongation factor 2 (eEF2). Findings from human and animal studies demonstrating an association between dysregulation of these pathways and AD pathophysiology are summarized and discussed.

scholarly journals MoniTORing neuronal excitability at the synapse

2013 ◽  
Vol 202 (1) ◽  
pp. 7-9 ◽  
Author(s):  
Inge Kepert ◽  
Michael A. Kiebler
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Potassium Channel ◽  
Molecular Mechanism ◽  
Neuronal Excitability ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Local Translation ◽  
Local Protein Synthesis ◽  
Local Protein

Mammalian target of rapamycin (mTOR) is a key player at the synapse regulating local translation and long-lasting synaptic plasticity. Now, a new study by Sosanya et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201212089) investigates the molecular mechanism of how mTOR suppresses local protein synthesis of a key potassium channel at activated synapses.

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

scholarly journals Long-Lasting Hyperexcitability Induced by Depolarization in the Absence of Detectable Ca2+ Signals

2009 ◽  
Vol 101 (3) ◽  
pp. 1351-1360 ◽  
Author(s):  
Kumud K. Kunjilwar ◽  
Harvey M. Fishman ◽  
Dario J. Englot ◽  
Roger G. O'Neil ◽  
Edgar T. Walters
Keyword(s):  
Protein Synthesis ◽  
Neuronal Injury ◽  
Adaptive Responses ◽  
Neuronal Responses ◽  
Local Protein Synthesis ◽  
Neuronal Viability ◽  
Nerve Ganglion ◽  
Dissociated Cell Culture ◽  
Activity Dependent

Learning and memory depend on neuronal alterations induced by electrical activity. Most examples of activity-dependent plasticity, as well as adaptive responses to neuronal injury, have been linked explicitly or implicitly to induction by Ca2+ signals produced by depolarization. Indeed, transient Ca2+ signals are commonly assumed to be the only effective transducers of depolarization into adaptive neuronal responses. Nevertheless, Ca2+-independent depolarization-induced signals might also trigger plastic changes. Establishing the existence of such signals is a challenge because procedures that eliminate Ca2+ transients also impair neuronal viability and tolerance to cellular stress. We have taken advantage of nociceptive sensory neurons in the marine snail Aplysia, which exhibit unusual tolerance to extreme reduction of extracellular and intracellular free Ca2+ levels. The axons of these neurons exhibit a depolarization-induced memory-like hyperexcitability that lasts a day or longer and depends on local protein synthesis for induction. Here we show that transient localized depolarization of these axons in an excised nerve–ganglion preparation or in dissociated cell culture can induce short- and intermediate-term axonal hyperexcitability as well as long-term protein synthesis–dependent hyperexcitability under conditions in which Ca2+ entry is prevented (by bathing in nominally Ca2+ -free solutions containing EGTA) and detectable Ca2+ transients are eliminated (by adding BAPTA-AM). Disruption of Ca2+ release from intracellular stores by pretreatment with thapsigargin also failed to affect induction of axonal hyperexcitability. These findings suggest that unrecognized Ca2+-independent signals exist that can transduce intense depolarization into adaptive cellular responses during neuronal injury, prolonged high-frequency activity, or other sustained depolarizing events.

scholarly journals Protein synthesis in the dendrite

2002 ◽  
Vol 357 (1420) ◽  
pp. 521-529 ◽  
Author(s):  
Shao Jun Tang ◽  
Erin M. Schuman
Keyword(s):  
Protein Synthesis ◽  
Neural Plasticity ◽  
Messenger Rna ◽  
Mrna Translation ◽  
Synaptic Activity ◽  
Synaptic Proteins ◽  
Local Source ◽  
Synaptic Protein ◽  
Specific Proteins ◽  
Molecular Nature

In neurons, many proteins that are involved in the transduction of synaptic activity and the expression of neural plasticity are specifically localized at synapses. How these proteins are targeted is not clearly understood. One mechanism is synaptic protein synthesis. According to this idea, messenger RNA (mRNA) translation from the polyribosomes that are observed at the synaptic regions provides a local source of synaptic proteins. Although an increasing number of mRNA species has been detected in the dendrite, information about the synaptic synthesis of specific proteins in a physiological context is still limited. The physiological function of synaptic synthesis of specific proteins in synaptogenesis and neural plasticity expression remains to be shown. Experiments aimed at understanding the mechanisms and functions f synaptic protein synthesis might provide important information about the molecular nature of neural plasticity.

Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography

US Neurology ◽  
2010 ◽  
Vol 05 (02) ◽  
pp. 21
Author(s):  
Rosario Sanchez-Pernaute ◽  
Anna-Liisa Brownell ◽  
◽  
Keyword(s):  
Positron Emission Tomography ◽  
Synaptic Plasticity ◽  
Metabotropic Glutamate Receptor ◽  
Mrna Translation ◽  
Synaptic Function ◽  
Emission Tomography ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Mglu5 Receptors

Metabotropic glutamate receptors (mGluR)s are G-protein-coupled receptors that function as modulators of synaptic function and glutamate transmission. Post-synaptically localized subtype 5 mGlu5 receptors are co-localized with adenosine A2a, dopamine, and N-methyl-D-aspartate (NMDA) receptors and regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity. Aberrant synaptic plasticity appears to be involved in a number of developmental and degenerative neuropsychiatric disorders, including Parkinson’s disease. Pharmacological modulation of mGluR5 could potentially open new therapeutic avenues for the treatment of such disorders, for both symptomatic and neuroprotective purposes. In this review, we summarize a series ofin vivostudies we performed in order to delineate the anatomical basis and functional role of mGluR5 antagonists in Parkinson’s disease models, taking advantage of high-resolution positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals. Our findings of a prevalent distribution of mGluR5 in the striatum and limbic structures and a significant binding enhancement following dopamine lesions support the role of mGlu5 receptors in modulating dopamine- and glutamate-dependent signaling and synaptic plasticity within the basal ganglia cortico–subcortical loops.

scholarly journals BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Emily Petrus ◽  
Hey-Kyoung Lee
Keyword(s):  
Synaptic Plasticity ◽  
Visual Cortex ◽  
Synaptic Transmission ◽  
Sensory Experience ◽  
Synaptic Function ◽  
Excitatory Synaptic Transmission ◽  
Early Gene ◽  
Dependent Manner ◽  
Homeostatic Synaptic Plasticity ◽  
Activity Dependent

Alzheimer’s disease (AD) is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (Aβ) peptides. Studies over the past few decades suggest that Aβis produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions forβ- andγ-secretases, the two key enzymes that produce Aβby sequentially processing the amyloid precursor protein (APP), have been discovered over recent years. In particular, activity-dependent production of Aβhas been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity “sensor,” which acts upstream of Aβproduction and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronalβ-secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.

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