Qualitative behavior and robustness of dendritic trafficking

Neural function depends on continual synthesis and targeted trafficking of intracellular components, including ion channel proteins. Many kinds of ion channels are trafficked over long distances to specific cellular compartments. This raises the question of whether cargo is directed with high specificity during transit or whether cargo is distributed widely and sequestered at specific sites. We addressed this question by experimentally measuring transport and expression densities of Kv4.2, a voltagegated transient potassium channel that exhibits a specific dendritic expression that increases with distance from the soma and little or no functional expression in axons. In over 500 h of quantitative live imaging, we found substantially higher densities of actively transported Kv4.2 subunits in axons as opposed to dendrites. This paradoxical relationship between functional expression and traffic density supports a model-commonly known as the sushi belt model-in which trafficking specificity is relatively low and active sequestration occurs in compartments where cargo is expressed. In further support of this model, we find that kinetics of active transport differs qualitatively between axons and dendrites, with axons exhibiting strong superdiffusivity, whereas dendritic transport resembles a weakly directed random walk, promoting mixing and opportunity for sequestration. Finally, we use our data to constrain a compartmental reaction-diffusion model that can recapitulate the known Kv4.2 density profile. Together, our results show how nontrivial expression patterns can be maintained over long distances with a relatively simple trafficking mechanism and how the hallmarks of a global trafficking mechanism can be revealed in the kinetics and density of cargo.

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“…However, the exact nature of the feedback signal is unknown. We therefore used the averaged delivery rate over all

, which amounts to simple proteostasis and is a realistic feedback signal in a neuron ( 54 ).…”

Section: Resultsmentioning

confidence: 99%

Paradoxical relationships between active transport and global protein distributions in neurons

Bellotti

Murphy

Lin

et al. 2021

Biophysical Journal

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“…Under such assumptions the analysis we developed here could provide a starting point for a model of local, distributed regulation. Further work, including our own ongoing work 73 , can connect such local regulation to the global regulation at the level an entire, spatially extended cell.…”

Section: Consequences Of Modeling Calcium Concentration Using a Singlmentioning

confidence: 99%

Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Gorur-Shandilya

Marder

O’Leary

2020

Sci Rep

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In many species, excitable cells preserve their physiological properties despite significant variation in physical size across time and in a population. For example, neurons in crustacean central pattern generators generate similar firing patterns despite several-fold increases in size between juveniles and adults. This presents a biophysical problem because the electrical properties of cells are highly sensitive to membrane area and channel density. It is not known whether specific mechanisms exist to sense membrane area and adjust channel expression to keep a consistent channel density, or whether regulation mechanisms that sense activity alone are capable of compensating cell size. We show that destabilising effects of growth can be specifically compensated by feedback mechanism that senses average calcium influx and jointly regulate multiple conductances. However, we further show that this class of growth-compensating regulation schemes is necessarily sensitive to perturbations that alter the expression of subsets of ion channel types. Targeted perturbations of specific ion channels can trigger a pathological response of the regulation mechanism and a failure of homeostasis. Our findings suggest that physiological regulation mechanisms that confer robustness to growth may be specifically vulnerable to deletions or mutations that affect subsets of ion channels.

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“…The second observation, derived from simulations, is that growth adaptation may compensate for pathological oscillations, enabling more aggressive synaptic scaling. Aggressive feedback gains k u may lead to pathological oscillations in synaptic scaling [9], as shown in Figure 6(a). However, these oscillations are dampened through growth adaptation, as shown in Figure 6(b), reaching the desired set-point.…”

Section: Homeostasis By Fast Synaptic Scaling and Slow Growth Adaptationmentioning

confidence: 99%

“…The synthesis process of ion channels and receptor proteins depends on a feedback signals, including calcium influx [6], [7]. Previous work showed that transport processes suffer from severe delays [8], and can pose a potential source of instability in the presence of cellular feedback control [9].…”

Section: Introductionmentioning

confidence: 99%

Dendritic trafficking: synaptic scaling and structural plasticity

Aljaberi¹,

O’Leary²,

Forni³

2020

Preprint

Self Cite

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Neuronal circuits internally regulate electrical signaling via a host of homeostatic mechanisms. Two prominent mechanisms, synaptic scaling and structural plasticity, are believed to maintain average activity within an operating range by modifying the strength and spatial extent of network connectivity using negative feedback. However, both mechanisms operate on relatively slow timescales and thus face fundamental limits due to delays. We show that these mechanisms fulfill complementary roles in maintaining stability in a large network. In particular, even relatively, slow growth dynamics improves performance significantly beyond synaptic scaling alone.

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Qualitative behavior and robustness of dendritic trafficking

Cited by 5 publications

References 21 publications

Paradoxical relationships between active transport and global protein distributions in neurons

Paradoxical relationships between active transport and global protein distributions in neurons

Activity-dependent compensation of cell size is vulnerable to targeted deletion of ion channels

Dendritic trafficking: synaptic scaling and structural plasticity

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