Kv4.3 Effects on Dendritic Integration

Since Kv4.3 channels are targeted to the somatodendritic compartment of neurons and are expressed in and around synapses (see introduction), these channels may alter

dendritic integration at pyramidal cell synapses. It is now well accepted that dendrites do not function as simple passive cables as previously suggested (Rall 1967). If they did behave in this manner, the cable properties of dendrites would cause synaptic potentials to attenuate as a function of the distance from the soma. In addition, there would be different time

integration windows for proximal and distal synapses (Magee 2000). With these properties, the neuron is only responsive to the quantity of excitatory input, and it would be difficult for a neuron to predictably fire a precisely timed action potential in response to recognizable

patterns of input.

However, dendritic specializations are now thought to produce dendritic potentials that defy cable properties (Yuste and Tank 1996). For example, dendrites can elicit spikes in response to excitatory input if they express either Ca2+ or Na+ channels and the input is temporally or spatially coincident (Gasparini et al. 2004; Losonczy and Magee 2006; Stuart and Sakmann 1994). In addition, these same studies demonstrated that dendritic potassium channels, like Kv4.2 and Kv4.3 or HCN channels, could attenuate excitatory input. Such conductances change the behavior of dendrites from a linear, integrative cable, to one that exhibits nonlinear output based on the spatiotemporal pattern of input (Magee 2000). For

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example, if EPSPs converge on a neuron close in space and time, the actual change in membrane potential at the soma is greater than would be predicted with a linear integration. Such supra-linearities could lead to short latency, well timed spikes by increasing the rising slope of the membrane potential (Azouz and Gray 2000; Gasparini et al. 2004). In contrast, Kv4.2 and HCN channels attenuate excitatory potentials. These dynamic properties benefit the neuron by conferring upon them a mechanism by which they can recognize and respond to patterns of input with precisely timed spikes and reduce ill-timed spikes fired in response to noisy or jittery input. Thus, it is the qualities, and not just the quantity of synaptic input that is encoded in the output.

Further, these dendritic conductances allow for modulation in the behavior of the neuron. This modulation could result from second messenger systems being activated by neuromodulators such as acetylcholine or norepinephrine (Hoffman and Johnston 1999) or by patterns of input, which engage different configurations of dendritic conductances (Berman and Maler 1998; Llinas and Sugimori 1980; Llinas 1988). Therefore, the neuron represents not just the synaptic input in to the cell, but also the condition of the neuron itself, which can be altered by both history of activity and neuromodulation. With these intrinsic properties, the neuron can respond to very specific changes in the information it must process and encode.

How could such mechanisms be useful in DCN pyramidal cells? We have already shown both in this work and previous work, that Kv4.3 confers a mechanism by which inhibitory inputs are encoded by the timing of spikes. After a period of inhibition, the same excitatory input will result in a delay in spike time compared to the timing without the previous inhibition. There is no doubt that inhibitory inputs play an essential role in

information encoding in the DCN. It is possible that Kv4.3 is responsible for the output patterns of pyramidal cells in response to patterns of inhibitory input.

In addition, Kv4.3 could provide a mechanism by which certain patterns of input lead to supra-linear behavior, while other patterns of input lead to sub-linear behavior. The state of the neuron would depend upon the patterns of input and neuromodulation. When there is strong inhibitory input, Kv4.3 would be available to activate. In this scenario Kv4.3 would attenuate any weak or spatiotemporally distant input further by opening its outward

conductance (sub-linear state). However, if there was very coincident input, it could overcome this opposition and lead to a well-timed spike (supra-linear state). The threshold for how spatiotemporally succinct these inputs would need to be could be set by history the history of activity or neuromodulation of the channel through phosphorylation. One possible mechanism for such neuromodulation is acetylcholine. It is known that the DCN receives cholinergic inputs (Chen et al. 1994; 1995). In addition, it is known that muscarinic stimulation leads to changes in Kv4 channel voltage sensitivity (Hoffman and Johnston 1999). Therefore, these cholinergic inputs in the DCN might supply some of the neuromodulation necessary for the neurons to switch between these two states.

By allowing the cell to be tuned to history of input and neuromodulation, Kv4.3 could provide the link between auditory and non-auditory inputs. Information about head position would push a pyramidal cell into a certain regime. When the pyramidal cells sense

subsequent auditory information, it is processed in terms of the sensory input that has placed certain constraints on the pyramidal cell. In this way, spectral notch information would be interpreted based on the head position. This mechanism would allow pyramidal cells to encode the auditory information along with non-auditory information.

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Channels other than Kv4.3 would certainly play a role in this type of information

encoding. Apical dendrites also express Ca2+ channels that, when activated, could boost any

excitatory input from auditory nerve fibers resulting in action potentials that would not have been elicited without the Ca2+ spikes. It is not known if apical or basal dendrites express Na+ channels but they could also perform the same role only faster. Pyramidal cells do express a low-threshold persistent Na+ current that, when activated, could boost synaptic excitation (Manis et al. 2003). Work in this area will prove very helpful in further understanding the role of spatiotemporal patterns of input and the auditory and non-auditory convergence onto pyramidal cells.