Bergmann glia modulate cerebellar Purkinje cell bistability via Ca ²⁺ -dependent K ⁺ uptake

Abstract

Recent studies have shown that cerebellar Bergmann glia display coordinated Ca 2+ transients in live mice. However, the functional significance of Bergmann glial Ca 2+ signaling remains poorly understood. Using transgenic mice that allow selective stimulation of glial cells, we report here that cytosolic Ca 2+ regulates uptake of K + by Bergmann glia, thus providing a powerful mechanism for control of Purkinje cell-membrane potential. The decline in extracellular K + evoked by agonist-induced Ca 2+ in Bergmann glia transiently increased spike activity of Purkinje cells in cerebellar slices as well as in live anesthetized mice. Thus, Bergmann glia play a previously unappreciated role in controlling the membrane potential and thereby the activity of adjacent Purkinje cells.two-photon laser scanning microscopy | ion-sensitive microelectrode B ergmann glial cells in cerebellum are electrically nonexcitable cells that in many ways serve the same functions as protoplasmic astrocytes in forebrain. Bergmann glia are chiefly responsible for glutamate uptake and extracellular K + homeostasis (1). Their highly negative resting membrane potential of −80 to −85 mV combined with a large number of inwardly rectifying K + channels helps maintain a tight control of extracellular K + concentration (2). Bergmann glial cells also display Ca 2+ transients in response to glutamate or stimulation of climbing and parallel fibers in slices and to motor activity in vivo (3). However, although glial Ca 2+ signaling has been shown to regulate synaptic transmission in several brain regions, it is presently not established whether Bergmann glia can modulate the activity of Purkinje cells.Membrane potentials of almost all neurons in mammalian brain fluctuate between a hyperpolarized state (down state) and depolarized state (up state) during sleep/anesthesia and quiet wakefulness (4, 5). These fluctuations of the membrane potentials are synchronized between neighboring cells and detected as slow (∼0.5-1 Hz), large-amplitude delta waves (4). Even though the existence of bistability of Purkinje cells in awake mice has been questioned, it is generally agreed that bistability is a common phenomenon in both anesthetized and sleeping animals (5). The bistability of the resting membrane potential in Purkinje cells was first discovered by Llinás and Sugimori in cerebellar slices (6, 7). The current model predicts that bistability of Purkinje cells, similar to thalamic neurons, relies on the balance between noninactivating inward currents (persistent Na + currents and/or T-type Ca 2+ currents) (4, 8, 9) and an outward K + leak current (5-7, 10). However, Purkinje cell bistability is not simply an expression of intrinsic membrane properties because complex spikes generated by climbing fiber activation can toggle the membrane potential between up and down states in vivo (5). Recently, glutamate uncaging on distal dendrites of striate spiny neurons was shown to induce up states that lasted hundreds of milliseconds (11), and small hyperpolarization current...

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