Brief increases in [Ca2+]i can result in prolonged changes in neuronal properties. A Ca(2+)-dependent modulation of the hyperpolarization-activated cation current (Ih) controls the slow recurrence of synchronized thalamocortical activity. Here we show that the persistent activation of Ih is initiated by rapidly increased [Ca2+]i and subsequent production of cAMP. The modulation is maintained via a facilitated interaction of cAMP with open (voltage-gated) h-channels, inducing prolonged activation of Ih that may outlast the presence of increased free [Ca2+]i and [cAMP]i. This persistent Ih activation may control the presence and periodicity of both normal and abnormal synchronized thalamocortical rhythms.