Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity

Abstract

Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.1 to Kv7.2. Due to the slow activation kinetics of Kv7.2, the redistribution of the Kv channels reduced the shunting conductance at the elongated AIS during the initiation of action potentials and effectively enhanced the excitability of the deprived neurons. The results indicate that the functional plasticity of the AIS works cooperatively with the structural plasticity and compensates for the loss of afferent inputs to maintain the homeostasis of auditory circuits after hearing loss by cochlea removal.

M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment

“…These discrepancies might be due to differences in cell types, species, strain, or experimental procedures, including the kind of antibodies or fixation conditions. For example, in the avian nucleus magnocellularis neurons, K v 7.2 immunoreactivity was distributed along the entire AIS (50). In agreement with our findings and in line with previous work (38,39), FGF14, which physically bridges the K v 7 and Na v channels and entirely localizes to the proximal AIS (38,39), exhibited a shorter length than that of ankyrin G (∼24 μm versus 33 μm) in our preparation (Fig.…”

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

“…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)(3)(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)(6)(7). Experimental studies linking changes in AIS length and neuronal output showed that an increased length facilitates AP generation (6,8).…”

Surface dynamics of voltage-gated ion channels

“…1,61,76 The tuning of the action potential threshold is critically dependent on the activity of voltage-gated calcium channels and the density and kinetic properties of Na V and K V channels. 1,77 Crucial questions, such as how channels are inserted into and removed from membranes and whether there are density gradients in Na v and K v channel expression along the AIS, can now be answered with the observation of channel dynamics in the membrane. Interestingly, both ion channel populations (Na V and K V ) are linked to the Ankyrin G scaffold via similar binding motifs.…”

“…18 Alterations to ion channel composition and AIS size are known mechanisms of neuronal excitability tuning. 1,77 It remains to be explored whether the surface dynamics of Na V and K V channels contribute to such alterations in AIS size or position.…”

“…105 Therefore, changes in the number and location of surface potassium channels can profoundly affect electrical excitability and neuronal plasticity. 52,77 Potassium channels comprise the largest, and at the molecular level the most diverse, class of ion channels, which contains over 80 genes encoding for the channel's principal (or a1) subunits. K v channels exist as multisubunit complexes formed by typically 4 a1 subunits (2 in case of 2-pore K v ) and variable number of associated auxiliary subunits.…”