Calcineurin Signaling Mediates Activity-Dependent Relocation of the Axon Initial Segment

Evans, Mark D.; Sammons, Rosanna P.; Lebron, Sabrina; Dumitrescu, Adna S.; Watkins, Thomas B.K.; Uebele, Victor N.; Renger, John J.; Grubb, Matthew S.

doi:10.1523/jneurosci.0277-13.2013

Cited by 118 publications

(195 citation statements)

References 85 publications

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“…We next sought to determine which calcium-activated effectors are involved in the glutamate-induced endocytosis. Calcineurin/PP2B has been shown to drive the distal movement of AIS during long-term depolarization (Evans et al, 2013). To examine whether it contributes to the endocytosis of Kv7.2/7.3, we pretreated SEP-TAC-7.3-expressing neurons with 1 M CsA before Glu/Gly exposure.…”

Section: Resultsmentioning

confidence: 99%

Live Imaging of Kv7.2/7.3 Cell Surface Dynamics at the Axon Initial Segment: High Steady-State Stability and Calpain-Dependent Excitotoxic Downregulation Revealed

et al. 2016

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The voltage-gated K ϩ channels Kv7.2 and Kv7.3 are located at the axon initial segment (AIS) and exert strong control over action potential generation. Therefore, changes in their localization or cell surface numbers are likely to influence neuronal signaling. However, nothing is known about the cell surface dynamics of Kv7.2/7.3 at steady state or during short-term neuronal stimulation. This is primarily attributable to their membrane topology, which hampers extracellular epitope tagging. Here we circumvent this limitation by fusing an extra phluorin-tagged helix to the N terminus of human Kv7.3. This seven transmembrane chimera, named super ecliptic phluorin (SEP)-TAC-7.3, functions and traffics as a wild-type (WT) channel. We expressed SEP-TAC-7.3 in dissociated rat hippocampal neurons to examine the lateral mobility, surface numbers, and localization of AIS Kv7.2/7.3 heteromers using live imaging. We discovered that they are extraordinarily stable and exhibit a very low surface mobility both during steady state and neuronal stimulation. In the latter case, we also found that neither localization nor cell surface numbers were changed. However, at high glutamate loads, we observed a rapid irreversible endocytosis of Kv7.2/7.3, which required the activation of NR2B-containing NMDA receptors, Ca 2ϩ influx, and calpain activation. This excitotoxic mechanism may be specific to ankyrin G-bound AIS proteins because Nav1.2 channels, but not AIS GABA A receptors, were also endocytosed. In conclusion, we have, for the first time, characterized the cell surface dynamics of a full-length Kv7 channel using a novel chimeric strategy. This approach is likely also applicable to other Kv channels and thus of value for the additional characterization of this ion channel subfamily.

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Section: Resultsmentioning

confidence: 99%

Live Imaging of Kv7.2/7.3 Cell Surface Dynamics at the Axon Initial Segment: High Steady-State Stability and Calpain-Dependent Excitotoxic Downregulation Revealed

et al. 2016

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“…During the first weeks of development, when the dendritic tree rapidly expands, the AIS also shifts from its distal site to a more proximal location near the soma (35) and dynamically changes in length (36). One mechanism identified for activitydependent changes in AIS location includes the Ca 2+ influx from L-type Ca 2+ channels subsequently activating the cytosolic signaling pathways, including the Ca 2+ -calmodulin-sensitive phosphatase calcineurin (37). Such a molecular mechanism may also be suitable to link local somatodendritic Ca 2+ elevations with cytoskeletal organization along the axon.…”

Section: Discussionmentioning

confidence: 99%

Covariation of axon initial segment location and dendritic tree normalizes the somatic action potential

Hamada

Goethals

Vries

et al. 2016

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

121

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In mammalian neurons, the axon initial segment (AIS) electrically connects the somatodendritic compartment with the axon and converts the incoming synaptic voltage changes into a temporally precise action potential (AP) output code. Although axons often emanate directly from the soma, they may also originate more distally from a dendrite, the implications of which are not wellunderstood. Here, we show that one-third of the thick-tufted layer 5 pyramidal neurons have an axon originating from a dendrite and are characterized by a reduced dendritic complexity and thinner main apical dendrite. Unexpectedly, the rising phase of somatic APs is electrically indistinguishable between neurons with a somatic or a dendritic axon origin. Cable analysis of the neurons indicated that the axonal axial current is inversely proportional to the AIS distance, denoting the path length between the soma and the start of the AIS, and to produce invariant somatic APs, it must scale with the local somatodendritic capacitance. In agreement, AIS distance inversely correlates with the apical dendrite diameter, and model simulations confirmed that the covariation suffices to normalize the somatic AP waveform. Therefore, in pyramidal neurons, the AIS location is finely tuned with the somatodendritic capacitive load, serving as a homeostatic regulation of the somatic AP in the face of diverse neuronal morphologies.T he axon initial segment (AIS) specifies in vertebrate neurons a single domain for the final integration of synaptic input and the initiation of action potentials (APs) (1, 2). To rapidly produce large inward and outward currents mediating the AP, the AIS contains a complex arrangement of cytoskeletal and transmembrane proteins clustering high densities of voltage-gated sodium (Nav) and potassium (Kv) channels in the axolemma (2-4). Although the composition of ion channels is critical for initiation and regulation of firing patterns, there are emerging insights that the AIS is not operating in isolation but is also subject to activity-dependent changes in size and location constrained by the local dendritic branch geometry and the passive cable properties (5-7). Experimental studies linking changes in AIS length and neuronal output showed that an increased length facilitates AP generation (6,8). In these cases, the net increased excitability is a logical consequence of the larger Nav conductance. However, predicting the impact of AIS location on neuronal output is more complex. Experimental studies showed that an activity-dependent distal shift of the AIS is associated with decreased AP output (5). In contrast, model simulations showed that shifting the AIS distally promotes excitability (9). One of the critical factors influencing AIS excitability is the large somatodendritic membrane area acting as current sink for sodium current generated in the AIS (10-12). In this view, a distal anatomical location of the AIS increases electrical compartmentalization and facilitates axonal AP generation. Indeed, the local depolarization in the...

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“…In addition, there is an ongoing debate as to whether axoaxonic synapses depolarize or hyperpolarize postsynaptic pyramidal neurons (14), although in conditions mimicking in vivo-like oscillations, they act mainly as inhibitors of excitability (15). The emerging picture is one where chandelier cells play an important role in modulating neuronal output at the AIS, but the precise way in which this happens remains to be properly established.More recently, longer-term forms of modulation have been described at the AIS in response to chronic alterations in neuronal activity (16)(17)(18)(19)(20). For example, sensory deprivation of chick brainstem auditory neurons caused an increase in the length of the AIS, which was paralleled by an increase in neuronal excitability (18).…”

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confidence: 99%

“…More recently, longer-term forms of modulation have been described at the AIS in response to chronic alterations in neuronal activity (16)(17)(18)(19)(20). For example, sensory deprivation of chick brainstem auditory neurons caused an increase in the length of the AIS, which was paralleled by an increase in neuronal excitability (18).…”

mentioning

confidence: 99%

“…For example, sensory deprivation of chick brainstem auditory neurons caused an increase in the length of the AIS, which was paralleled by an increase in neuronal excitability (18). Conversely, in dissociated hippocampal neurons, increases in neuronal activity through either application of hyperkaelimic solution or by optogenetic means resulted in the distal relocation of the AIS, which correlated with a decrease in excitability (16,17). These exciting forms of structural and functional plasticity have raised many questions that remain unanswered.…”

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confidence: 99%

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Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output

Wefelmeyer

Cattaert

Burrone

2015

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

105

104

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The axon initial segment (AIS) is a structure at the start of the axon with a high density of sodium and potassium channels that defines the site of action potential generation. It has recently been shown that this structure is plastic and can change its position along the axon, as well as its length, in a homeostatic manner. Chronic activitydeprivation paradigms in a chick auditory nucleus lead to a lengthening of the AIS and an increase in neuronal excitability. On the other hand, a long-term increase in activity in dissociated rat hippocampal neurons results in an outward movement of the AIS and a decrease in the cell's excitability. Here, we investigated whether the AIS is capable of undergoing structural plasticity in rat hippocampal organotypic slices, which retain the diversity of neuronal cell types present at postnatal ages, including chandelier cells. These interneurons exclusively target the AIS of pyramidal neurons and form rows of presynaptic boutons along them. Stimulating individual CA1 pyramidal neurons that express channelrhodopsin-2 for 48 h leads to an outward shift of the AIS. Intriguingly, both the pre-and postsynaptic components of the axo-axonic synapses did not change position after AIS relocation. We used computational modeling to explore the functional consequences of this partial mismatch and found that it allows the GABAergic synapses to strongly oppose action potential generation, and thus downregulate pyramidal cell excitability. We propose that this spatial arrangement is the optimal configuration for a homeostatic response to long-term stimulation.axon initial segment | chandelier cells | optogenetics | intrinsic plasticity | homeostatic plasticity N eurons receive a large number of synaptic inputs along the somato-dendritic compartment that integrate at the axon initial segment (AIS) to fire an action potential (AP) (1-3). As an important site for transforming graded synaptic inputs into all-or-none APs, it is also a potentially sensitive target for the modulation of neuronal excitability (4, 5). In fact, one interesting aspect of principal neurons in the hippocampus and cortex is the presence of a unique type of GABAergic axo-axonic synapse that forms onto the AIS and controls neuronal output (6, 7). These synapses are formed by a specific group of fast-spiking interneurons, the chandelier cells, that are generally found sparsely distributed in the brain and have therefore been difficult to study in the past (6, 8). However, the recently developed transgenic mouse lines that can label chandelier neurons more selectively have begun to shine light on their form and function (9). In the cortex, the axonal "cartridges" of synaptic boutons that form onto the AIS are generally found on the more distal AIS domain, where the AP is thought to initiate (9). Although there is little information on the role of these interneurons in network function, they have been implicated in a number of events, including driving negative feedback in the dentate gyrus (10), modulating the emergence of sha...

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Calcineurin Signaling Mediates Activity-Dependent Relocation of the Axon Initial Segment

Cited by 118 publications

References 85 publications

Live Imaging of Kv7.2/7.3 Cell Surface Dynamics at the Axon Initial Segment: High Steady-State Stability and Calpain-Dependent Excitotoxic Downregulation Revealed

Live Imaging of Kv7.2/7.3 Cell Surface Dynamics at the Axon Initial Segment: High Steady-State Stability and Calpain-Dependent Excitotoxic Downregulation Revealed

Covariation of axon initial segment location and dendritic tree normalizes the somatic action potential

Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output

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