Long-term potentiation
In neuroscience, long-term potentiation (LTP) refers to an extended period (minutes to hours) of increased synaptic strength that typically follows high-frequency stimulation of a synapse. The phenomenon was discovered in the mammalian hippocampus by Terje Lømo in 1966 and is popularly regarded as the cellular basis of memory.
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2 Discovery and characterization 3 Models of LTP 4 Errors in sufficiency and necessity trials 5 Related topics 6 References |
LTP, particularly Hebbian LTP, classically exhibits four main properties: rapid induction, cooperativity, associativity, and input specificity:
LTP was first observed by Terje Lømo in 1966 in the Oslo, Norway, laboratory of Per Andersen. There, Lømo conducted a series of neurophysiological experiments exploring the role of the hippocampus in rat short-term memory. Targeting the synapses between granule cells of the perforant pathway and those of the dentate gyrus, Lømo elicited excitatory postsynaptic potentials (EPSPs) from dentate gyrus cells by stimulating the perforant pathway. He observed that a high-frequency train of stimulation produced larger, prolonged EPSPs compared to the responses evoked by a single stimulation. This phenomenon was soon dubbed "long-term potentiation".
Timothy Bliss, who joined the Andersen laboratory in 1969, collaborated with Lømo in 1973 to publish the first characterization of LTP in rabbit hippocampus.
One can imagine a finite number of ways in which the strength of a synapse might be enhanced. In brief, either 1) the presynaptic cell releases more neurotransmitter, 2) the postsynaptic cell's sensitivity to neurotransmitter is increased, or 3) both occur simultaneously.
Until recent years, modern LTP research, driven by Nobel laureate Eric Kandel, focused on the presynaptic cell as the sole participant in the induction and maintenance of LTP [1]. Many such studies employed a simplified preparation of the marine snail Aplysia californica and analyzed the neurophysiology of its siphon-withdrawal reflex, finding that strong depolarization of presynaptic sensory neurons was sufficient for eliciting a prolonged and heightened postsynaptic response. Other studies of presynaptic cells revealed an increased number of neurotransmitter vesicles at facilitated synapses. Moreover, studies of the facilitatory role of the postsynaptic cell demonstrated that activation of the postsynaptic motor neuron was neither sufficient nor necessary for the induction of LTP [1]. Together, these studies gave rise to the popular notion that the presynaptic neuron was exclusively responsible for the facilitation of the postsynaptic response—a phenomenon known as activity-dependent presynaptic facilitation.
In 1949, neuroscientist Donald Hebb introduced Hebbian theory, a possible mechanism of synaptic plasticity, putting forth the so-called "neurophysiological postulate". With regard to long-term potentiation, Hebb's theory suggests that simultaneous activity of both pre- and postsynaptic cells is necessary for the induction of LTP. Indeed, modern work by David Glanzman [1] as well as Kandel [1] and many others support the role of a Hebbian process in the induction of LTP in Aplysia sensorimotor synapses. (See Errors in sufficiency and necessity trials for an illustration of why previous work failed to recognize the role of the postsynaptic cell in LTP induction.)
This Hebbian LTP depends critically on the function of the NMDA receptor located on the postsynaptic cell. NMDA receptors are associative molecules, able to detect simultaneous activity in the pre- and postsynaptic cell. Only when both neurons are active does the NMDA receptor allow Ca2+ to flow into the postsynaptic cell, initiating a cascade of events including postsynaptic modification (e.g., growth of new dendritic spines and insertion of new glutamate receptors into the postsynaptic membrane) and the activation of the presynaptic cell via an unidentified retrograde messenger. This messenger serves to activate protein kinases (e.g., cAMP-dependent protein kinase A) which would enhance presynaptic neurotransmitter release and thus further facilitate the postsynaptic response.
In 1984, Carew et al demonstrated that postsynaptic activity was neither sufficient nor necessary for the induction of LTP [1]. Sufficiency experiments were carried out by stimulating the postsynaptic cell body with strong depolarizing current and then recording EPSPs that resulted from weak presynaptic stimulation. Researchers did not find the enhanced EPSPs previously observed with strong presynaptic depolarization alone, yielding the conclusion that postsynaptic activation was not sufficient to induce LTP.
In the necessity trials, a strong hyperpolarizing current was injected into the postsynaptic cell body while intense depolarizing current was applied to the presynaptic cell. The investigators' rationale was that if postsynaptic activity was required for the induction of LTP, then such strong hyperpolarizing current applied to the postsynaptic cell would prevent LTP induction. Indeed, researchers found instead that hyperpolarization of the postsynaptic cell did not prevent the induction of LTP, giving rise to the notion that postsynaptic activity was not necessary for LTP induction.
One source of error in the sufficiency and necessity experiments by Carew et al was that stimulation to the postsynaptic cell was consistently applied to the cell body rather than the postsynaptic density where synapses were made. Investigators thus made the incorrect assumption that the current applied to the soma would travel across neurites to the postsynaptic site without significant dissipation. However, the electrotonic distance between the soma and the postsynaptic density is quite large, resulting in significant dissipation of current by the time the postsynaptic site is reached. A reasonable explanation for the results of Carew et al is that the relevant synaptic sites on the postsynaptic cell were never depolarized during the sufficiency trials, and were never hyperpolarized in the necessity trials. Thus Carew et al received results in direct opposition to those of Lin and Glanzman, who successfully demonstrated that the postsynaptic cell was both sufficient and necessary for the induction of LTP [1].
Properties of LTP
Discovery and characterization
Models of LTP
Activity-dependent presynaptic facilitation
Hebbian LTP
Errors in sufficiency and necessity trials
Related topics
References