Spike patterning by Ca2+-dependent regulation of a muscarinic cation current in entorhinal cortex layer II neurons

In entorhinal cortex layer II neurons, muscarinic receptor activation promotes depolarization via activation of a nonspecific cation current (I-NCM). Under muscarinic influence, these neurons also develop changes in excitability that result in activity-dependent induction of delayed firing and bursting activity. To identify the membrane processes underlying these phenomena, we examined whether I-NCM may undergo activity-dependent regulation. Our voltage-clamp experiments revealed that appropriate depolarizing protocols increased the basal level of inward current activated during muscarinic stimulation and suggested that this effect was due to I-NCM upregulation. In the presence of low buffering for intracellular Ca2+, this upregulation was transient, and its decay could be followed by a phase of I-NCM downregulation. Both up- and downregulation were elicited by depolarizing stimuli able to activate voltage-gated Ca2+ channels (VGCC); both were sensitive to increasing concentrations of intracellular Ca2+-chelating agents with downregulation being abolished at lower Ca2+-buffering capacities; both were reduced or suppressed by VGCC block or in the absence of extracellular Ca2+. These data indicate that relatively small increases in [Ca2+](i) driven by firing activity can induce upregulation of a basal muscarinic depolarizing-current level, whereas more pronounced [Ca2+](i) elevations can result in I-NCM downregulation. We propose that the interaction of activity-dependent positive and negative feedback mechanisms on I-NCM allows entorhinal cortex layer II neurons to exhibit emergent properties, such as delayed firing and enhanced or suppressed responses to repeated stimuli, that may be of importance in the memory functions of the temporal lobe and in the pathophysiology of epilepsy.