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

Abstract

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...

Homeostatic Plasticity of Subcellular Neuronal Structures: From Inputs to Outputs

“…Recent work has explored activity-dependent forms of plasticity at the AIS to establish whether these axoaxonic synapses follow the structural modifications described above. Surprisingly, relocation of the AIS after chronic stimulation did not result in a change in synapse location in either dissociated hippocampal neurons or hippocampal slices 58, 59, resulting in a mismatch between the two. From a functional point of view, modelling results revealed that this arrangement actually helps to reduce neuronal excitability levels.…”

“…In hippocampal neurons, a different strategy is used. It is now well established that either 2 days of optogenetic photostimulation or high potassium depolarisation leads to a cell-autonomous outward shift of the AIS in excitatory neurons 52, 57, 58, 59, accompanied by a reduction in intrinsic excitability 52, 59. This form of structural plasticity that spatially translocates the AIS to a more distal domain in response to increased activity is dependent on calcium influx through L-type calcium channels and activation of the calcium-sensitive phosphatase calcineurin [57].…”

Structural and Functional Plasticity at the Axon Initial Segment

“…(B) In hippocampal dentate granule cells, depolarization for 3 h shortens the AIS but simultaneously de-phosphorylates voltage-gated Na + (Nav) channels, which offsets the effects of shortening on excitability (Evans et al, 2015). (C) In hippocampal CA1 pyramidal neurons, depolarization for 2 days moves the AIS distally, but axo-axonic synapses remain at the original location, augmenting the suppressive effects of distal movement on excitability (Wefelmeyer et al, 2015). …”

“…Although this movement is not accompanied by changes in the ion channel composition at the AIS (Grubb and Burrone, 2010), nor in the location of axo-axonic GABAergic synapses (Figure 1C; Wefelmeyer et al, 2015), it results in a spatial mismatch between the axo-axonic synapses and the AIS, augmenting the suppressive effects of the AIS movement. This augmentation occurs because the remaining synapses increase the shunting conductance between the soma and the AIS and reduce the charges reaching the AIS.…”

Evaluating Tools for Live Imaging of Structural Plasticity at the Axon Initial Segment

“…Over longer timescales of hours to days, the structural and positional features of the AIS can also undergo modifications in response to sustained perturbations in neuronal activity. These structural forms of AIS plasticity—which can include changes in AIS length, position and/or ion channel distribution in both excitatory and inhibitory neurons (Grubb and Burrone, 2010a; Kuba et al, 2010; Muir and Kittler, 2014; Chand et al, 2015; Evans et al, 2015; Wefelmeyer et al, 2015)—have been shown to be associated with changes in neuronal excitability, and may form part of a repertoire of compensatory mechanisms acting to maintain network activity within set limits.…”