Brief increases in [Ca 2+] i can result in prolonged changes in neuronal properties. A Ca 2+-dependent modulation of the hyperpolarization-activated cation current (I h) controls the slow recurrence of synchronized thalamocortical activity. Here we show that the persistent activation of I h is initiated by rapidly increased [Ca 2+] 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 I h that may outlast the presence of increased free [Ca 2+] i and [cAMP] i. This persistent I h activation may control the presence and periodicity of both normal and abnormal synchronized thalamocortical rhythms.