Art - McCormick (D)

Activity-induced transient increases in intracellular Ca2+ concentration ([Ca]i) trigger neuronal responses ranging from modulation of synaptic transmission to alterations in gene expression with time courses of seconds to days1–3. These changes occur through Ca2+-stimulated messenger cascades that can induce prolonged recruitment of proteins by, for example, autophosphorylation4, persistent binding to Ca2+/calmodulin5 or transcription factor activation6. Increased [Ca]i may also affect the intrinsic electrical characteristics of neurons by modifying properties of ionic channels7, through, for example, Ca2+-triggered activation of kinases or adenylyl cyclases. However, because few studies (for example, ref. 8) have quantitatively investigated the temporal relationship between activity-dependent [Ca]i elevation and its effects on ionic conductances in intact central neurons, how much these modulations may contribute to persistent changes in neuronal circuits is unclear. Hyperpolarization-activated cation currents (Ih) are widely expressed in the nervous system and often function as ‘pacemaker’ currents for rhythmic electrical behavior9–11. The role of Ih is well characterized in thalamocortical cells, where this current not only contributes to rhythmic discharges of single neurons, but also governs the slow periodic recurrence of network activities10–13. Thalamic synchronized oscillations in the form of spindle waves appear as 1–4-second periods of synchronized activity interspersed by silent phases of 5–20 seconds14. The oscillatory period arises as a cyclical interaction between thalamocortical cells and inhibitory neurons from the nucleus reticularis thalami (nRT) or perigeniculate nucleus (PGN)15. Burst firing in nRT/PGN neurons induces rhythmic IPSPs in thalamocortical cells, which, in turn, generate rebound low-threshold Ca2+ spikes and bursts of action potentials that re-excite the nRT/PGN neurons. The silent period between spindle waves is largely determined by persistent Ih activation in thalamocortical cells 12,13,16. This activation, initiated during the oscillatory period, causes thalamocortical cells to generate a slowly decaying (tens of seconds) afterdepolarization (ADP)12 that prevents the generation of rebound bursts, thereby stopping the oscillations. This persistent Ih activation is induced partly by transient [Ca ]i increases resulting from rebound Ca2+ spikes during the oscillations16. Although the time course of the silent period between these oscillations in vitro is largely controlled by the slow decay of the ADP12,13, what determines the temporal dynamics of persistent Ih activation remains unclear. Here we show that Ih enters a state of Ca2+-independent persistent activation via allosterically stabilized interaction with cAMP released upon Ca2+ entry, thus indicating a direct relationship between ionic channel function and slow network activity10.