Neurons are highly polarized cells with apparent functional and morphological differences between dendrites and axon. A critical determinant for the molecular and functional identity of axonal and dendritic segments is the restricted expression of voltage-gated ion channels (VGCs). Several studies show an uneven distribution of ion channels and their differential regulation within dendrites and axons, which is a prerequisite for an appropriate integration of synaptic inputs and the generation of adequate action potential (AP) firing patterns. This review article will focus on the signaling pathways leading to segmented expression of voltage-gated potassium and sodium ion channels at the neuronal plasma membrane and the regulatory mechanisms ensuring segregated functions. We will also discuss the relevance of proper ion channel targeting for neuronal physiology and how alterations in polarized distribution contribute to neuronal pathology.

Summary The capacity to distinguish comparable experiences is fundamental for the recall of similar memories and has been proposed to require pattern separation in the dentate gyrus (DG). However, the cellular mechanisms by which mature granule cells (GCs) of the DG accomplish this function are poorly characterized. Here, we show that Kv4.2 channels selectively modulate the excitability of medial dendrites of dentate GCs. These dendrites are targeted by the medial entorhinal cortex, the main source of spatial inputs to the DG. Accordingly, we found that the spatial pattern separation capability of animals lacking the Kv4.2 channel is significantly impaired. This points to the role of intrinsic excitability in supporting the mnemonic function of the dentate and to the Kv4.2 channel as a candidate substrate promoting spatial pattern separation.