Kv3.1 channels stimulate adult neural precursor cell proliferation and neuronal differentiation. (12th April 2013)

• Record Type: Journal Article
• Authors: Yasuda, Takahiro; Cuny, Hartmut; Adams, David J.
• Is Part Of: Journal of physiology. Volume 591:Number 10(2013:May)
• Page Start: 2579
• Page End: 2591
• Publication Date: 2013-04-12
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2012.249151
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>In the adult mammalian brain, neural precursor cells (NPCs) play an important role in neuronal plasticity.</p> </list-item> <list-item> <label> </label> <p>Although adult NPCs exhibit voltage‐gated, delayed rectifier K<sup>+</sup> (K<sub>DR</sub>) channel currents, the K<sub>DR</sub> channel subtype dominantly expressed in adult NPCs and its functional role have not been defined.</p> </list-item> <list-item> <label> </label> <p>Using gene knockdown targeting K<sub>v</sub>3.1 K<sup>+</sup> channels, we show K<sub>v</sub>3.1 is a dominant K<sub>DR</sub> subtype expressed in adult NPCs.</p> </list-item> <list-item> <label> </label> <p>K<sub>v</sub>3.1 knockdown significantly decreased adult NPC proliferation and reduced differentiation into neuroblasts.</p> </list-item> <list-item> <label> </label> <p>Our findings provide new insight into a mechanism of adult neurogenesis and suggest that selective activation of K<sub>v</sub>3.1 in adult NPCs may be a new therapeutic approach to treating neurodegenerative diseases.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> Adult neural stem/precursor cells (NPCs) play a pivotal role in neuronal plasticity throughout life. Among ion channels identified in adult NPCs, voltage‐gated delayed rectifier K<sup>+</sup> (K<sub>DR</sub>) channels are dominantly expressed. However, the K<sub>DR</sub> channel subtype and its physiological role are still undefined. We used real‐time quantitative RT‐PCR and gene knockdown techniques to identify a major functional K<sub>DR</sub> channel subtype in adult NPCs. Dominant mRNA expression of K<sub>v</sub>3.1, a high voltage‐gated K<sub>DR</sub> channel, was quantitatively confirmed. K<sub>v</sub>3.1 gene knockdown with specific small interfering RNAs (siRNA) for K<sub>v</sub>3.1 significantly inhibited K<sub>v</sub>3.1 mRNA expression by 63.9% (<italic>P</italic> < 0.001) and K<sub>DR</sub> channel currents by 52.2% (<italic>P</italic> < 0.001). This indicates that K<sub>v</sub>3.1 is the subtype responsible for producing K<sub>DR</sub> channel outward currents. Resting membrane properties, such as resting membrane potential, of NPCs were not affected by K<sub>v</sub>3.1 expression. K<sub>v</sub>3.1 knockdown with 300 n<sc>m</sc> siRNA inhibited NPC growth (increase in cell numbers) by 52.9% (<italic>P</italic> < 0.01). This inhibition was attributed to decreased cell proliferation, not increased cell apoptosis. We also established a convenient <italic>in vitro</italic> imaging assay system to evaluate NPC differentiation using NPCs from doublecortin‐green fluorescent protein transgenic mice. K<sub>v</sub>3.1 knockdown also significantly reduced neuronal differentiation by 31.4% (<italic>P</italic> < 0.01). We have demonstrated that K<sub>v</sub>3.1 is a dominant functional K<sub>DR</sub> channel subtype expressed in adult NPCs and plays key roles in NPC proliferation and neuronal lineage commitment during differentiation.</p> </abstract>