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WIKIPEDIA BIO154/254: Molecular and Cellular Neurobiology

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Briefs of Long Term Potentiation(LTP)

What Long Term Potentiation is

A short high-frequency train of stimuli to any of the three major synaptic pathways in the hippocampus increases the amplitude of the excitatory postsynaptic potentials in the target hippocampal neurons. This facilitation is termed long term potentiation (LTP). LTP modifies synaptic effectiveness, which contributes to neural plasticity and thus memory.

Triggering of LTP

The triggering of LTP in the CA1 region of hippocampus depends on influx of Ca2+ through postsynaptic NMDA receptors. NMDA receptors only conduct Ca2+ when glutamate binds to postsynaptic NMDA receptor and the membrane potential of the postsynaptic cell is sufficiently depolarized so that Mg2+ can be repelled from the mouth of the receptor. The influx of Ca2+ triggers a series of biochemical reactions which eventually modifies the synaptic effectiveness. However, whether Ca2+ is sufficient for enhancement of synaptic effectiveness is still unclear.

Basic Properties of LTP

LTP is input specific, which means when LTP enhances the synaptic effectiveness in a certain set of synapses, it does not occur in other synapses in the same cell. This property is advantageous because it greatly increases the storage capacity of individual neurons.
LTP is cooperative, which means weak stimulations in a single pathway can cooperatively induce LTP.
LTP is associative, which means weak stimulation in many pathways can induce LTP.Assoiativivity of the LTP can be viewed as a cellular analog of classical conditioning.

Two phases of LTP

LTP has a transient early (lasting 1-3 hours) and a consolidated later phase (at least 24 hours). The transient early phase does not require new protein synthesis. For example, in early phase the conductance of the postsynaptic receptors is enhanced. The later phase requires new protein and RNA synthesis. For example, new presynaptic active zones and postsynaptic receptors can grow in the late phase.

Bolshakov and his colleagues shows that he early and late phases of LTP are evident in the synaptic transmission between a single CA3 cell and a single CA1 cell. (Images and captions are adaped from Ref 2.)

Experimental Setup: a single CA3 cell can be stimulated selectively to produce a single elementary synaptic potential in a CA1 cell. When the CA3 cell is stimulated repeatedly at low frequency, it gives rise to either an elementary response of the size of a miniature synaptic potential or a failure. In control cells there are many failures, the synapse has a low probability of releasing vesicles. The distribution of the amplitudes of many responses can be approximated by two Gaussian curves, one centered on zero (the failures) and the other centered on 4pA (the successful responses.) These histograms are consistent with the type of synapse illustrated here, in which a single CA3 cell makes a single connection on a CA1 cell. This connection has a single active zone from which it releases a single vesicle in an all-or-none manner (failures or successes).

With the early phase of LTP the probability of release rises significantly, but the two Gaussian curves in the distribution of responses is consistent with the view that a single release site still releases only a vesicle but now with a higher probability of release.

When the late phases of LTP is induced by a cAMP analog, the distribution of responses no longer fits two Gaussian curves but instead requires three or four Gaussian curves, suggesting the possibility that new presynaptic active zones and postsynaptic receptors have grown These effects are blocked by anisomycin, an inhibitor of protein synthesis.

Signal Transduction in LTP

Signal transduction in LTP is very complicated and many candidate molecules have been identified. However, only a few molecules play a mandatory role in signal transduction in LTP. One of them is α-calcium-calmodulin– dependent proteinkinase II (CaMKII). Postsynaptic inhibition of CaMKII or a genetic deletion of a critical subunit of CaMKII stops the induction of LTP. During the transient phase of LTP, CaMKII is activated by calcium-camodulin complex, and it enhaces the activity of existing AMPA receptors, phosphorylates intracellular AMPARs and activate Syn GAP and the MAPK cascade, which facilitates the inseration of new AMPARs into the postsynaptic membrane. Several other protein kinases, including protein kinase C (PKC), cyclic adeonosine 39,59-monophosphate (cAMP)–dependent protein kinase (PKA), the tyrosine kinase Src, and mitogen-activated protein kinase (MAPK), have also been suggested to contribute to LTP.

Simplifed model for the expression of LTP. An increase in Ca21 within the dendritic spine binds to calmodulin (CaM) to activate CaMKII, which undergoes autophosphorylation, thus maintaining its activity after Ca21 returns to basal levels. CaMKII phosphorylates AMPA receptors (AMPARs) already present in the synaptic plasma membrane, thus increasing their single-channel conductance. CaMKII is also postulated to inßuence the subsynaptic localization of AMPA receptors such that more AMPA receptors are delivered to the synaptic plasma membrane. The localization of these ÒreserveÓ AMPA receptors is unclear, and thus they are shown in three different possible locations. Before the triggering of LTP, some synapses may be functionally silent in that they contain no AMPA receptors in the synaptic plasma membrane. Nevertheless, the same expression mechanisms would apply. Adapted from Ref3.

Current Debate

Whether the increase in synaptic strength is primarily due to pre or postsynaptical is currently under debate. Current experimental data supports both. For instance, in the transient phase of LTP, there is an increase in the sensitivity and number of postsynaptic non-NMDA (AMPA) receptors to glutamate; also there is an increase in the probability of neurotransmitter release from the presynaptic side.

Reference

1. Terje Lømo (2003). "The discovery of long-term potentiation". Philos Trans R Soc Lond B Biol Sci 358 (1432): 617-20. PMID 12740104.
2. E.R. Kandel, J.H. Schwartz, T.M. Jessell, "Principles of Neural Science." 4th edition.
3. R. C. Malenka and a. R. A. Nicoll. "Long-Term Potentiation--A Decade of Progress?" Science, September 17, 1999; 285(5435): 1870 - 1874.
4. Lynch, MA. Long-Term Potentiation and Memory. Physiol Rev 84: 87–136, 2004; 10.1152/physrev.00014.2003

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