Synapse to nucleus signaling: is Ca2+ all you need?

The control of gene expression in response to specific synaptic activity is widely thought to be a crucial mechanism involved in many brain processes. Activity dependent gene expression mediated by the transcription factor CREB (cAMP-response-element-binding protein) is believed to be important in stabilizing long-term learning and memory. Full CREB activation requires both phosphorylation of serine 133 in addition to activation of the coactivator of CREB, CREB-binding protein (CBP). The nuclear located Ca2+/calmodulin-dependent kinase IV (CaMKIV) is a key mediator of both of these processes. But the question is, how does the signal of electrical activation at the synapse translate into an instruction for CaMKIV in the nucleus to activate the expression of genes? Current opinion maintains that the Ca2+ binding protein, calmodulin, which has been activated by Ca2+ entry following synaptic activation, is translocated into the nucleus and thereby influences gene expression. However, the findings of Hardingham et al. 1xNuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Hardingham, G.E. et al. Nat. Neurosci. 2001; 3: 261–267Crossref | Scopus (331)See all References1 provide a new twist to this story, as they report that Ca2+ alone is sufficient to relay synaptic activation to the regulation of CREB in the nucleus, and nuclear import of cytoplasmic signaling proteins is not necessary in this process.Hardingham et al. first demonstrated that in their experimental system of cultured primary hippocampal neurons, cytoplasmically-injected tagged calmodulin accumulated in the nucleus independently of synaptic activity and as such is unlikely to be a useful mediator of electrical activity signaling in these cells. The authors then injected wheat germ agglutinin into the cytoplasm to block nuclear protein import through the nuclear pore complex. Under these conditions electrical activity-dependent CREB activation was still detected, indicating that nuclear import of proteins was not required to transmit synaptically evoked signals to the nucleus via CaMKIV. Furthermore, they showed that elevating Ca2+ in isolated nuclei was sufficient to trigger signaling to CREB. The authors then showed that Ca2+ influx, through NMDA receptors, resulted in Ca2+-induced Ca2+ release from internal stores. This cytoplasmic Ca2+ release is proposed to amplify and relay the transient Ca2+ elevation at the synapse to an increase in Ca2+ concentration in the nucleus. It was observed that the nuclear Ca2+ concentration elevations peaked just after, and were longer lasting than, the corresponding transient dendritic Ca2+ increase. As a corollary to this finding, when bursts of synaptic activation to the hippocampal neurons were induced at higher frequency, nuclear Ca2+ remained at higher levels for a longer time through a progressive accumulation of burst-induced Ca2+ elevations. This was shown to result in a corresponding increase in CREB-mediated transcription.In this study the authors demonstrated that synaptic input frequency plays a significant role in nuclear Ca2+ dynamics and, by extension, to changes in gene expression. This finding suggests a mechanism for the interpretation of frequency information from synaptic inputs to long-term physiological modifications in the neuron. This mechanism is based on the retention of a synaptically induced Ca2+ signal by the nuclear transcription apparatus. The finding that synaptically-evoked Ca2+ increases in the nucleus were sufficient to activate CREB makes Ca2+ levels in the nucleus a strong candidate as a key player in complex neurobiological events, including learning, memory and cognitive processes.