Synaptic Tagging and Capture: Differential Role of Distinct Calcium/Calmodulin Kinases in Protein Synthesis-Dependent Long-Term Potentiation

Abstract

Weakly tetanized synapses in area CA1 of the hippocampus that ordinarily display long-term potentiation lasting ϳ3 h (called early-LTP) will maintain a longer-lasting change in efficacy (late-LTP) if the weak tetanization occurs shortly before or after strong tetanization of an independent, but convergent, set of synapses in CA1. The synaptic tagging and capture hypothesis explains this heterosynaptic influence on persistence in terms of a distinction between local mechanisms of synaptic tagging and cell-wide mechanisms responsible for the synthesis, distribution, and capture of plasticity-related proteins (PRPs). We now present evidence that distinct CaM kinase (CaMK) pathways serve a dissociable role in these mechanisms. Using a hippocampal brain-slice preparation that permits stable long-term recordings in vitro for Ͼ10 h and using hippocampal cultures to validate the differential drug effects on distinct CaMK pathways, we show that tag setting is blocked by the CaMK inhibitor KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) that, at low concentration, is more selective for CaMKII. In contrast, the CaMK kinase inhibitor STO-609 [7H-benzimidazo(2,1-a)benz(de)isoquinoline-7-one-3-carboxylic acid] specifically limits the synthesis and/or availability of PRPs. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders and test stimulation over long periods of time after LTP induction enable a pharmacological dissociation of these distinct roles of the CaMK pathways in late-LTP and so provide a novel framework for the molecular mechanisms by which synaptic potentiation, and possibly memories, become stabilized.

Asymmetrical Synaptic Cooperation between Cortical and Thalamic Inputs to the Amygdale

“…We found that weak cortical stimulation led to the induction of a transient form of LTP, which can be converted into a longlasting form of LTP by subsequent strong stimulation of the thalamic input. Similar to what has been described in hippocampal Schaffer collateral to CA1 synapses (Frey and Morris, 1998a;Frey and Morris, 1998b;Redondo et al, 2010), the thalamic-to-cortical synaptic cooperation is blocked by protein synthesis inhibition, strengthening the view that the sharing and capture of PRPs by the activated cortical and thalamic inputs underlies the conversion of the transient cortical LTP into a long-lasting LTP. We found that the cooperation between the cortical and thalamic inputs is bidirectional but the temporal constraints are asymmetrical.…”

“…Thus, we favor the hypothesis that the duration of the tag, ie, its activity to capture the PRPs, is shorter in weak thalamic stimulation as compared with weak cortical stimulation. Although the identity of the 'synaptic tag' remains elusive, recent studies suggest that the 'synaptic tag' should be seen as a temporary structural and/or functional state of the synapse, independent of the direction of the plastic change of the synapse and the molecular mechanisms involved in the maintenance of this plastic change (Fonseca, 2012;Redondo et al, 2010;Redondo and Morris, 2011). In this functional purview, any cellular mechanism that constrains the expression of synaptic plasticity, eg, from permissive to nonpermissive, is a component of the synaptic tag.…”

“…As mentioned previously, the synaptic tagging and capture hypothesis proposes a cellular mechanism that enables the association of events separated in time (Fonseca et al, 2004;Frey and Morris, 1998a;Redondo et al, 2010). To test whether cortical and thalamic inputs cooperate, we stimulated the cortical inputs with a weak stimulation protocol and assessed whether subsequent strong stimulation of the thalamic input is sufficient to convert the transient cortical LTP (E-LTP) into a long-lasting LTP (L-LTP).…”

“…A second possibility is that the activity of the 'synaptic tag' induced by the thalamic E-LTP induction had a shorter duration. Previous studies have reported a decrease of the ability of the 'synaptic tag' to capture PRPs with time but within a relative large time window of about 1 h (Frey and Morris, 1998b;Redondo et al, 2010;Fonseca, 2012). To test whether the time interval between E-LTP induction in thalamic synapses and the L-LTP induction in cortical synapses had an impact on cortical-to-thalamic cooperation, we repeated the experiment described above but reduced the time interval to 15 and 7.5 min.…”

“…LTP maintenance is achieved by an interaction between input-specific 'synaptic tags', set by LTP induction, and the capture of PRPs synthesized in the soma or local dendritic domains. These are independent processes and can occur separately in time (Fonseca et al, 2004;Govindarajan et al, 2011;Redondo et al, 2010). Thus, according to the synaptic tagging and capture hypothesis, the maintenance of synaptic plasticity is a function of neuronal network activity and not only of the input stimulated at a given time.…”