Ca2+/cAMP-Sensitive Covariation ofIAandIHVoltage Dependences Tunes Rebound Firing in Dopaminergic Neurons

Amendola, Julien; Woodhouse, Adele; Martin‐Eauclaire, Marie‐France; Goaillard, Jean-Marc

doi:10.1523/jneurosci.5297-11.2012

Cited by 99 publications

(216 citation statements)

References 60 publications

(143 reference statements)

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“…Furthermore, activity-dependent changes in synapses and in VGICs underlying some functional maps have shown to be governed by the same underlying signaling mechanisms (3,(41)(42)(43)(44)(45), imposing additional dependencies on the covariance among these functional maps. Finally, there is experimental evidence from several systems for activity-dependent and independent mechanisms of maintaining the coexpression of specific conductances (13,15,(46)(47)(48)(49)(50)(51)(52)(53). How do we reconcile these observations with the absence of strong pairwise correlations (Fig.…”

Section: Discussionmentioning

confidence: 96%

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

Rathour

Narayanan

2014

Proc. Natl. Acad. Sci. U.S.A.

239

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The maintenance of ion channel homeostasis, or channelostasis, is a complex puzzle in neurons with extensive dendritic arborization, encompassing a combinatorial diversity of proteins that encode these channels and their auxiliary subunits, their localization profiles, and associated signaling machinery. Despite this, neurons exhibit amazingly stereotypic, topographically continuous maps of several functional properties along their active dendritic arbor. Here, we asked whether the membrane composition of neurons, at the level of individual ion channels, is constrained by this structural requirement of sustaining several functional maps along the same topograph. We performed global sensitivity analysis on morphologically realistic conductance-based models of hippocampal pyramidal neurons that coexpressed six well-characterized functional maps along their trunk. We generated randomized models by varying 32 underlying parameters and constrained these models with quantitative experimental measurements from the soma and dendrites of hippocampal pyramidal neurons. Analyzing valid models that satisfied experimental constraints on all six functional maps, we found topographically analogous functional maps to emerge from disparate model parameters with weak pairwise correlations between parameters. Finally, we derived a methodology to assess the contribution of individual channel conductances to the various functional measurements, using virtual knockout simulations on the valid model population. We found that the virtual knockout of individual channels resulted in variable, measurementand location-specific impacts across the population. Our results suggest collective channelostasis as a mechanism behind the robust emergence of analogous functional maps and have significant ramifications for the localization and targeting of ion channels and enzymes that regulate neural coding and homeostasis. C hannel homeostasis, or channelostasis, refers to the regulation of the density, kinetics, voltage dependence, binding interactions, and the subcellular localization of individual ion channel types within a given cell [compared to proteostasis (1)]. Hippocampal CA1 pyramidal neurons are endowed with complex dendritic morphology and express numerous voltage-gated ion channels (VGICs), which govern critical neuronal functions across their somatodendritic arbor (2-6). Channelostasis in such neurons is an exceptionally complex puzzle, given the enormous morphological and molecular complexities accompanied by a myriad of subcellular channel localization profiles, resulting in an immense combinatorial diversity in channel expression profiles (4, 7-11). A further conundrum that compounds this complex puzzle is that neurons, despite these underlying complexities, exhibit amazingly regular gradients in several functional properties that manifest as maps along a continuous neuronal topograph (3). The coexistence of all these topographically continuous maps along the same neuronal topograph is mediated by intricately regulated subcellular l...

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Section: Discussionmentioning

confidence: 96%

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

Rathour

Narayanan

2014

Proc. Natl. Acad. Sci. U.S.A.

239

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“…As noted previously, the total potassium current flowing during the action potential repolarization is larger than the net outward current, because inward calcium current also flows during the action potential repolarization (Puopolo et al, 2007). In the experiment of Figure 7A, we followed the application of paxilline and GxTX-1E by applying a solution designed to inhibit all potassium currents, in which sodium was replaced by 155 mM TEA, together with 10 mM 4-aminopyridine and the Kv4-channel blocker AmmTx3 (Vacher et al, 2002;Amendola et al, 2012). This solution blocked additional outward current compared with paxilline and GxTX-1E together, revealing an inward current, likely carried by calcium channels, during the falling phase of the action potential.…”

Section: Action Potential-evoked Bk and Kv2 Currents In Dissociated Nmentioning

confidence: 99%

“…In general, the relationship between the ion channels found in a cell and the cell's electrical input-output properties is complex and impossible to predict a priori. In some circumstances, very different sets of ion channel populations can produce similar outputs; in others, small modulations in even one conductance can lead to dramatic changes in overall excitability (Goldman et al, 2001;Swensen and Bean, 2005;Amendola et al, 2012). In mammalian central neurons, there is a particularly large number and diversity of voltageactivated and calcium-activated potassium channels (Vacher et al, 2008), which help confer different firing properties on different types of neurons (Johnston et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

2015

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Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current ( f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The crossregulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell.

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“…A recent paper published in The Journal of Neuroscience (Amendola et al, 2012) capitalized on this perspective to uncover a novel form of covariation in the properties of I A and I H , potentially revealing the functional role of the observed relationship between these channels and suggesting that consideration of maximal conductance is not enough. Amendola et al (2012) examined the properties of I A and I H in dopaminergic neurons of the substantia nigra (SN) in rat midbrain slice preparations.…”

mentioning

confidence: 99%

“…Amendola et al (2012) examined the properties of I A and I H in dopaminergic neurons of the substantia nigra (SN) in rat midbrain slice preparations. Although these conductances are quite different and in opposition, they converge on the neuronal behavior of postinhibitory rebound firing to tune the cell's response to inhibitory inputs.…”

mentioning

confidence: 99%

Correlated Voltage Dependences of Ion Channels Revealed: Figure 1.

Hamood

Goeritz²

2012

J. Neurosci.

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Ca²⁺/cAMP-Sensitive Covariation ofI_AandI_HVoltage Dependences Tunes Rebound Firing in Dopaminergic Neurons

Cited by 99 publications

References 60 publications

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

Correlated Voltage Dependences of Ion Channels Revealed: Figure 1.

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