Synaptic Plasticity II: Location of the plasticity switch and a mechanism for synaptic tagging

Various types of synaptic plasticity have been demonstrated over these past 30 years, most notably Long-Term Potentiation (LTP) and Long-Term Depression (LTD), and their established characteristics and induction requirements are highly indicative of this plasticity being the substrate for memory formation. The molecular, biochemical and even structural models of synaptic plasticity that have been proposed in the past attempt to attribute the primary role of the plasticity switch to certain dual-character molecules, such as Ca++-dependent Calmodulin kinase II (CaM-KII). Although, at least in the CA1 hippocampal region, CaM-KII's activation is required for the induction of LTP, and this does occur only in an elevated Ca++ environment, all the previous anatomic, molecular, biochemical and structural models fail to provide us with the links between molecular modifications and the decreased electrophysiological response observed in the case of synaptic depression. These models also fail in answering any of the other persisting questions as well.

After organizing the established requirements to induce, consolidate and express hippocampal LTP and LTD, the existing models were evaluated on the basis of how they are able to accommodate all the accumulated data. The existing models were carefully deconstructed, their valid parts completed, if needed, and combined into a newly crystallized unified model. The proposed model demonstrates unified characteristics, as it is able to merge with the accepted structural model for metasynaptic LTP in the hippocampus and is able to answer at least two of the persisting questions regarding synaptic plasticity in the CA1 hippocampal region that were left unanswered by the previous models, namely: (a) the location of the plasticity switch that will determine the direction of the plasticity modification, and (b) a functional mechanism for synaptic targeting of the protein products required for the consolidation of long-term synaptic plasticity.

The central role in the unified model is reserved for the differential microconcentrations of Ca++ in specific spinal and dendritic locations. Even a brief and transient influx and increase in [Ca++] near the postsynaptic region is sufficient to trigger the polymerization of actin filaments and the perforation and augmentation of the postsynaptic membrane area. Provided that the influx persists however, the Ca++ will diffuse towards the spinal base from where the microconcentrations will precipitate the uptake of protein products (such as receptors and ionchannels) that are required to render the augmented synaptic area functional and, thus, more readily excited. This amounts to Short-Term Potentiation.

For the maturation of this STP into LTP to occur, persistent and summating EPSP's are required in order for the V-membrane to depolarize enough for the Voltage-Dependent-Calcium-Channels (VDCC's) to activate and the influx of Ca++ to reach the base of the spine. The increase of the [Ca++] at the base of the spine functions as the tagging signal for spines containing synapses under potentiation, that is the functional synaptic targeting mechanism for the protein products and mRNA required for the consolidation of LTP.

In the case of the induction of LTD by a Low Frequency Stimulation, the brief and transient influx of Ca++ is enough to augment the membrane area but not to render it functional with the insertion of more receptors and ion-channels. Thus, the synapse becomes harder to activate as its electrical resistance Rm has increased (due to increase in the membrane area without corresponding increase in its conductance). If the absense of HFS persists, the synapse stabilizes into depotentiation in order to avoid being functionally destroyed by repeated membrane area augmentations that would have rendered it practically impossible to activate in the future - and seriously hinder the plasticity modification of synapses in neighboring spines as well.

Key words: Memory, hippocampus, synaptic plasticity, long-term potentiation, LTP, long-term depotentiation, LTD, plasticity switch.