A Transient, Neuron-Wide Form of CREB-Mediated Long-Term Facilitation Can Be Stabilized at Specific Synapses by Local Protein Synthesis

Abstract

In a culture system where a bifurcated Aplysia sensory neuron makes synapses with two motor neurons, repeated application of serotonin (5-HT) to one synapse produces a CREB-mediated, synapse-specific, long-term facilitation, which can be captured at the opposite synapse by a single pulse of 5-HT. Repeated pulses of 5-HT applied to the cell body of the sensory neuron produce a CREB-dependent, cell-wide facilitation, which, unlike synapse-specific facilitation, is not associated with growth and does not persist beyond 48 hr. Persistent facilitation and synapse-specific growth can be induced by a single pulse of 5-HT applied to a peripheral synapse. Thus, the short-term process initiated by a single pulse of 5-HT serves not only to produce transient facilitation, but also to mark and stabilize any synapse of the neuron for long-term facilitation by means of a covalent mark and rapamycin-sensitive local protein synthesis.

Synapse-specific stabilization of plasticity processes: The synaptic tagging and capture hypothesis revisited 10 years later

“…Similarly, experiments in cultured Aplysia neurons also demonstrated that capture of LTF was possible within a discrete time window from 1-2 hours before to 1-4 hours after the induction of LTF in the opposite branch by five pulses of serotonin (Casadio et al, 1999).…”

“…These critical experiments were later independently replicated by Frey's (Sajikumar and Frey, 2004a) and Morris's (O'Carroll and Morris, 2004) groups, and by other labs working both in the mammalian hippocampus (Young and Nguyen, 2005) and in Aplysia neuronal cultures (Casadio et al, 1999). They arguably represent the strongest evidence supporting the STC model.…”

“…Thus, elegant electrophysiology experiments in the rodent hippocampus and in Aplysia cultured neurons have dissected synaptic tagging and activity-driven gene expression, showing that, as inferred by the STC model, tags in different inputs can be set independently and prior to the induction of gene expression ( Figure 2E) (Casadio et al, 1999;Frey and Morris, 1998b). Whereas other experiments demonstrated that transcriptional activation can prime LTP consolidation in the absence of synaptic tagging ( Figure 2F) (Barco et al, 2002;Casadio et al, 1999;Dudek and Fields, 2002).…”

“…The STC hypothesis revisited 20 candidate mechanisms for the tag (Barco et al, 2002;Casadio et al, 1999;Sajikumar et al, 2007a;Sajikumar et al, 2005;Young et al, 2006). Activity regulated kinases meet all the criteria for a synaptic tag: their activity can be spatially restricted by membrane anchoring, the half-life of protein phosphorylation is consistent with the temporal span of tag activity (few hours), and they can interact with a variety of substrates and modulate E-LTP.…”

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

“…One study demonstrated that low dose rapamycin leads to NMDA-dependent induction of long-term potentiation (LTP) in CA1 neurons of rat hippocampal slices when paired with weak presynaptic stimulation (Terashima et al, 2000). In contrast, others have shown that rapamycin impairs LTP by inhibiting mTOR through reduced protein synthesis (Casadio et al, 1999;Tang et al, 2002). Finally, a third study demonstrated that rapamycin did not affect LTP at baseline, and did not prevent the inhibition of LTP by H 2 O 2 (20 µM) (Kamsler and Segal, 2003).…”