A multi-omics view of neuronal subcellular protein synthesis

Sun, Chao; Schuman, Erin M.

doi:10.1016/j.conb.2023.102705

Cited by 11 publications

(10 citation statements)

References 71 publications

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“…First and foremost, intuitively, there should exist cell biological mechanisms that allow an individual synapse to control its own gene products, i.e., the proteins. 19 Take a single hippocampal neuron, for example. It can host >10000 synapses in an expansive dendritic and axonal arbor that extends hundreds of microns.…”

Section: Within Synapsesmentioning

confidence: 99%

“…First and foremost, intuitively, there should exist cell biological mechanisms that allow an individual synapse to control its own gene products, i.e. , the proteins . Take a single hippocampal neuron, for example.…”

Section: Investigating Cell Biological Processes Within Synapsesmentioning

confidence: 99%

“…Recent translatomics data contain averaged kinetic information for thousands of mRNA species in dendrites and axons using ex situ methods. , To study the translation of these mRNAs in situ , single-particle tracking has become a powerful tool, especially in combination with advanced mRNA labeling techniques such as SunTags and molecular beacons. ,, Single-particle tracking is a live-cell microscopy technique that records the dynamics of fluorescently tagged molecules (or particles) in situ with fast imaging frequency ( e.g ., <50 ms). In postprocessing, a trace is created for each tagged molecule to capture its motion in space and time (Figure B bottom).…”

Section: Investigating Cell Biological Processes Within Synapsesmentioning

confidence: 99%

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Single-Molecule-Resolution Approaches in Synaptic Biology

Sun

2024

J. Phys. Chem. B

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Synapses between neurons are the primary loci for information transfer and storage in the brain. An individual neuron, alone, can make over 10000 synaptic contacts. It is, however, not easy to investigate what goes on locally within a synapse because many synaptic compartments are only a few hundred nanometers wide in size�close to the diffraction limit of light. To observe the biomolecular machinery and processes within synapses, in situ singlemolecule techniques are emerging as powerful tools. Guided by important biological questions, this Perspective will highlight recent advances in using these techniques to obtain in situ measurements of synaptic molecules in three aspects: the cell-biological machinery within synapses, the synaptic architecture, and the synaptic neurotransmitter receptors. These advances showcase the increasing importance of single-molecule-resolution techniques for accessing subcellular biophysical and biomolecular information related to the brain.

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Section: Within Synapsesmentioning

confidence: 99%

Section: Investigating Cell Biological Processes Within Synapsesmentioning

confidence: 99%

Section: Investigating Cell Biological Processes Within Synapsesmentioning

confidence: 99%

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Single-Molecule-Resolution Approaches in Synaptic Biology

Sun

2024

J. Phys. Chem. B

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“… 257 ) Polyribosomes are elevated at the spine base and necks, 258 ) and many synaptic proteins, such as CaMKII, β-actin, PSD95, and AMPA receptors, are ready to be translated in the dendrites. 259 )…”

Section: Activity-dependent Structural Plasticity (P2: Extrinsic Dyna...mentioning

confidence: 99%

Unraveling the mysteries of dendritic spine dynamics: Five key principles shaping memory and cognition

KASAI

2023

Proc. Jpn. Acad., Ser. B

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Recent research extends our understanding of brain processes beyond just action potentials and chemical transmissions within neural circuits, emphasizing the mechanical forces generated by excitatory synapses on dendritic spines to modulate presynaptic function. From in vivo and in vitro studies, we outline five central principles of synaptic mechanics in brain function: P1: Stability – Underpinning the integral relationship between the structure and function of the spine synapses. P2: Extrinsic dynamics – Highlighting synapse-selective structural plasticity which plays a crucial role in Hebbian associative learning, distinct from pathway-selective long-term potentiation (LTP) and depression (LTD). P3: Neuromodulation – Analyzing the role of G-protein-coupled receptors, particularly dopamine receptors, in time-sensitive modulation of associative learning frameworks such as Pavlovian classical conditioning and Thorndike’s reinforcement learning (RL). P4: Instability – Addressing the intrinsic dynamics crucial to memory management during continual learning, spotlighting their role in “spine dysgenesis” associated with mental disorders. P5: Mechanics – Exploring how synaptic mechanics influence both sides of synapses to establish structural traces of short- and long-term memory, thereby aiding the integration of mental functions. We also delve into the historical background and foresee impending challenges.

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“…Our work extends upon studies that investigated local transcriptomes and translation in the context of formation 29,36,[108][109][110][111][112] , maintenance [113][114][115] , and plasticity of synapses [116][117][118][119] . These studies have established the need for subcellularly distinct transcriptomes and local translation for pre-and post-synaptic function (reviewed in 120 ).…”

Section: Comparative Transcriptomics Of Cell Bodies and Gcs Isolated ...mentioning

confidence: 99%

Dynamic subtype- and context-specific subcellular RNA regulation in growth cones of developing neurons of the cerebral cortex

Veeraraghavan,

Engmann,

Hatch

et al. 2023

Preprint

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Long range projection neurons of the cerebral cortex provide multimodal integration via connectivity between distant areas of the brain, thus are critical for sensory integration, motor processing, and higher cognitive function. During development, distinct subtypes of cortical projection neurons extend their axons to widely distinct areas within the cortex and beyond, sometimes projecting multiple axons simultaneously with precision to several target regions. Correct connectivity is achieved via axon guidance implemented by a growth cone (GC) at the leading tip of each axon. Prior work has identified that local protein synthesis of axonally-trafficked transcripts is required for directional responses to at least some guidance cues, but how distinct subtype- and projection-specific GCs establish, maintain, and regulate their subtype-specific subcellular molecular machinery is essentially unknown. Here we investigate the composition and dynamic regulation of subcellular transcriptomes of two subtypes of cortical projection neurons, with distinct connectivity and function. We compare GC-localized transcriptomes between interhemispheric, callosal projection neurons and corticothalamic projection neurons and across developmental stages, and find pronounced overlap, likely reflecting shared subcellular machinery. Intriguingly, we find that GC-localized transcriptomes of these subtypes of projection neurons are enriched for genes associated with neurodevelopmental and neuropsychiatric diseases. We then focus on context-specific portions of GC-localized transcriptomes, and identify known and novel potential regulators of distinct phases of circuit development: long-distance growth, gray matter innervation, and synapse formation. Next, we investigate mechanisms by which transcripts are enriched in GCs and dynamically regulated, and find evidence for GC-enriched motifs in 3 prime untranslated regions. As an exemplar, we identify cytoplasmic adenylation element binding protein 4 (CPEB4) as potentially regulating localization and translation of mRNAs encoding molecular machinery important for axonal branching and complexity. Additionally, we identify RNA binding motif single stranded interacting protein 1 (RBMS1) as a dynamically expressed regulator of RNA stabilization that enables successful callosal circuitry formation. Elucidation of context-specific subcellular RNA localization, and likely stability, is a critical advance toward a mechanistic understanding of local GC processes involved in circuit development, maintenance, and function. Even subtle changes in the precision of associative and integrative cortical circuits can have pronounced effects on cortical function, and lead to neurodevelopmental and neuropsychiatric disorders. Thus, integrated knowledge of GC- and soma-localized molecular controls involved in circuit formation will be necessary to fully understand the etiologies of these diseases and enable targeted therapeutics.

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A multi-omics view of neuronal subcellular protein synthesis

Cited by 11 publications

References 71 publications

Single-Molecule-Resolution Approaches in Synaptic Biology

Single-Molecule-Resolution Approaches in Synaptic Biology

Unraveling the mysteries of dendritic spine dynamics: Five key principles shaping memory and cognition

Dynamic subtype- and context-specific subcellular RNA regulation in growth cones of developing neurons of the cerebral cortex

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