Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na+ channels (Nav 1.2 and Nav 1.6) and voltage-gated K+ channels (Kv 4 and Kv 7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsy-chiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development

Axon-somatic back-propagation in detailed models of spinal alpha motoneurons

Antidromic action potentials following distal stimulation of motor axons occasionally fail to invade the soma of alpha motoneurons in spinal cord, due to their passing through regions of high non-uniformity. Morphologically detailed conductance-based models of cat spinal alpha motoneurons have been developed, with the aim to reproduce and clarify some aspects of the electrophysiological behavior of the antidromic axon-somatic spike propagation. Fourteen 3D morphologically detailed somata and dendrites of cat spinal alpha motoneurons have been imported from an open-access web-based database of neuronal morphologies, NeuroMorpho.org, and instantiated in neurocomputational models. An axon hillock, an axonal initial segment and a myelinated axon are added to each model. By sweeping the diameter of the axonal initial segment (AIS) and the axon hillock, as well as the maximal conductances of sodium channels at the AIS and at the soma, the developed models are able to show the relationships between different geometric and electrophysiological configurations and the voltage attenuation of the antidromically traveling wave. In particular, a greater than usually admitted sodium conductance at AIS is necessary and sufficient to overcome the dramatic voltage attenuation occurring during antidromic spike propagation both at the myelinated axon-AIS and at the AIS-soma transitions