Long-Term Depression in Hippocampus Research Paper

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Hippocampal LTD is a form of activity-dependent synaptic plasticity where the cumulative activation of inputs to specific neural pathways in the hippocampus produces a decrease in the excitability of the activated neurons. Several forms of hippocampal LTD have been identified, and much research has examined the mechanisms by which LTD is expressed in the hippocampus. In this research paper, a characterization of hippocampal LTD and its possible involvement for memory storage in the mammalian brain will be examined.

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1. Synaptic Plasticity in the Hippocampus

Synaptic plasticity is a term used to describe several forms of long-lasting, activity-dependent changes in synaptic strength. The importance of synaptic plasticity is due to the presumption that information, or memories, are stored in the brain as complex spatialtemporal patterns of neuronal activity that occur in large ensembles of neurons. Learning, defined as any type of experience-dependent change in sensory processing or experience-dependent change in behavior, is thought to involve the storage of new information via a process that involves long-lasting changes in synaptic strength in the circuits that were activated during the learning process. Synaptic plasticity is also important for the development of neural circuitry, because an initial activity-independent phase occurs during which axons grow into their target regions and produce an overabundance of synaptic contacts followed by an activity-dependent phase during which some of the synapses are strengthened and consolidated, while other synapses are weakened and pruned away.

During the early 1970s, the discovery of long-term potentiation (LTP), a long-lasting enhancement of synaptic activity that follows a brief, high-frequency electrical stimulation, provided strong experimental evidence for a model of synaptic plasticity associated with a number of important functions of the nervous system, including learning and memory. When LTP was first identified, it was most reliably and robustly elicited in the hippocampus, an integral component of the medial-temporal lobe system that mediates a number of very important forms of declarative memory (Squire 1987). LTP can be reliably elicited in intact in vivo preparations, as well as in reduced in itro preparations, making it amenable to detailed experimental manipulation and analysis.

If synapses in the hippocampus simply continued to increase in strength as a result of LTP, all synapses would eventually reach some level of maximum efficacy. At this point, it would be difficult or impossible, at least in principle, to encode new information. Moreover, active synapses would be so plentiful that even a small stimulus would excite many cells, resulting in pathologies like epilepsy. To make synaptic strengthening a useful mechanism for encoding information, other processes must selectively weaken specific sets of synapses. LTD in the hippocampus may be an example of just such a process.

2. Hippocampal Anatomy and Circuitry

The hippocampus provides a useful model system for the study of synaptic plasticity on both anatomical and electrophysiological grounds. The hippocampus is divided into two major subpopulations of neurons: the hippocampus proper, composed primarily of pyramidal cells (subdivided into four subfields: CA1– CA4), and the dentate gyrus, composed primarily of granule cells.

A series of discrete, anatomical units called lamellae oriented along the transverse axis of the structure compose the hippocampus (Andersen et al. 1971). It is this lamellar organization that allows for the precision in identification of known stimulation and recording sites within the hippocampal trisynaptic circuit. Stimulation of perforant path fibers of the entorhinal cortex, which provides the main input into the lamellae of the hippocampus, results in the activation of granule cells of the dentate gyrus. Stimulation of the granule cells, in turn, activates the pyramidal cells of the CA3 region through the mossy fiber system. The axons of the CA3 pyramidal cells bifurcate, sending an efferent stimulus through their main branch out through the fimbria to the fornix, and a collateral branch (Schaffer collaterals) sweeping upward to synapse on the apical dendrites of CA1 pyramids. The sequential activation of this trisynaptic circuit has been verified both anatomically and electrophysiologically (Swanson et al. 1982).

The Schaffer collateral-CA1 pyramidal cell synapse is one of the best understood synapses in the mammalian brain, and many of the currently known phenomena of synaptic plasticity, including shortterm potentiation, LTP, paired pulse facilitation, and LTD, have been found to occur at this synapse.

3. Two Forms of Hippocampal LTD

Two basic forms of hippocampal LTD have been distinguished. Homosynaptic LTD occurs only when the strengths of active synapses are depressed, e.g., homosynaptic LTD can occur at synapses that are given low-frequency electrical stimulation. Heterosynaptic LTD occurs only when the strengths of inactive synapses are depressed, e.g., heterosynaptic LTD can occur at synapses that are inactive during high-frequency stimulation of a converging synaptic input. Heterosynaptic LTD was discovered in the dentate gyrus in i o in 1979, with evidence for homosynaptic LTD in area CA1 reported in 1992. In this research paper, hippocampal LTD will be described by first focusing on homosynaptic LTD in area CA1, followed by a discussion of heterosynaptic LTD in the dentate gyrus.

3.1 Homosynaptic LTD in area CA1

Homosynaptic LTD has been studied in itro in the excitatory monosynaptic pathway running from the Schaffer collaterals (afferents) to area CA1 cells. In the paradigm most often used to induce homosynaptic LTD, the delivery of several hundred electrical stimuli to the Schaffer collaterals at low frequencies produces a sustained depression of modest but significant magnitude in area CA1 cells. The key properties of homosynaptic LTD produced by lowfrequency stimulation are summarized below (see Bear and Abraham 1996, Dudek and Bear 1992, Mulkey and Malenka 1992):

(a) Low frequency stimulation-induced LTD is input specific. Only synapses receiving low-frequency conditioning stimulation show LTD; other synaptic inputs converging onto the same population of postsynaptic neurons are unaffected (hence the term homosynaptic LTD).

(b) Low-frequency stimulation-induced LTD is frequency dependent. LTD depends on the frequency of conditioning stimulation. LTD usually results from 0.5–3 Hz stimulation, but the same number of pulses at higher frequencies can produce LTP instead.

(c) Low-frequency stimulation-induced LTD is saturable and reversible. Repeated episodes of lowfrequency stimulation in CA1 saturate LTD. Furthermore, synapses that are depressed can be potentiated, and vice versa, indicating that LTD is not a result of lasting damage to the stimulated synapses.

(d) Low-frequency stimulation-induced LTD usually requires N-methyl--aspartate (NMDA) receptor activation. Under most circumstances, NMDA receptor antagonists reversibly block homosynaptic LTD.

3.2 Heterosynaptic LTD in Dentate Gyrus

Heterosynaptic LTD has been studied in i o in the excitatory monosynaptic pathway running from layer II cells of the entorhinal cortex via the perforant path to the granule cells of the dentate gyrus; it has not yet been observed in itro. Like LTP in the hippocampus, heterosynaptic LTD is saturable and reversible, and, depending on stimulation parameters, can last for days or weeks. In most experiments, the induction of heterosynaptic LTD in one pathway is accompanied by LTP of the path that was tetanized. This fact, plus the failure to observe this form of LTD in itro, has restricted investigations of the mechanisms specifically underlying heterosynaptic LTD.

Long-Term Depression in Hippocampus Research Paper

4. Mechanisms of Hippocampal LTD Induction

In most cases, hippocampal LTD requires activation of glutamate receptors and postsynaptic calcium (Ca +) ion influx at the site of synaptic contact in the dendritic spine. Biochemically, hippocampal LTD also appears to require activation of protein phosph atases, which may be preferentially activated by Ca + influx. Interestingly, the magnitude of synaptically-evoked changes in postsynaptic Ca + concentration appears to dictate whether LTP or LTD is elicited.

4.1 Receptor Acti ation

Synaptically-released glutamate can activate several types of glutamate receptors, presumably co-localized at individual synaptic contacts at individual dendritic spines. One of these is the NMDA receptor; another is the α-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate (AMPA) receptor. During basal synaptic transmission, the current that generates hippocampal synaptic responses is due to activation of the AMPA receptor, which is associated with sodium-potassium channels. The channels open briefly, sodium ions rush in, and the excitatory postsynaptic potential develops. This glutamate-AMPA transmitter-receptor is the prototypic fast excitatory synapse in the brain.

Long-Term Depression in Hippocampus Research Paper

Although the NMDA receptor is a glutamate receptor, it is not activated by weak synaptic actions like that of the AMPA receptor, and therefore contributes very little to changes in the membrane potential during basal synaptic transmission. However, when the cell is depolarized by various patterns of synaptic activation, magnesium ions leave the channels, and glutamate activation of th e NMDA receptors opens the channels allowing Ca²⁺ to rush into the neuron because unlike AMPA rec eptors, NMDA receptors are highly permeable to Ca²⁺. There is strong evid ence that the NMDA receptor-mediated change in Ca²⁺ is a necessary, and perhaps sufficient trigger for both LTP and LTD. Hippocampal homosynaptic LTD is reversibly blocked by the NMDA receptor antagonist DL-2amino-5-phosphonovaleric acid, and is also blocked by strong hyperpolarization during the hype rpolarization protocol or buffering postsynaptic Ca²⁺ (Bear and Malenka 1994, Kemp and Bashir 1997, Mulkey and Malenka 1992). This evidence sug gests that NMDA receptor-dependent changes in Ca²⁺ might be the primary mechanism by which hippocampal LTD is mediated.

While much has been learned about the mechanisms of NMDA-dependent hippocampal LTD, there is some additional evidence that another type of glutamate receptor, the metabotropic glutamate receptor (mGluR), might also play a key role in establishing LTD, particularly during early postnatal life (Bolshakov and Siegelbaum 1994). This receptor would be classed as having a slow or modulatory action: it does not directly control ion channels, but controls a second-messenger system via a G protein that acts on the intracellular biochemical machinery of the cell. One of the primary functions of mGluRs in synaptic transmission is to provide activity-dependent autoinhibition through presynaptic suppression of transmitter release (Glaum and Miller 1994). Activation of mGluRs results in reversible depression in the strength of synaptic input to principal neurons in the trisynaptic hippocampal circuitry, and in the presence of mGluR antagonists, LTD is inhibited, as well as mRNA translation, which suggests that protein synthesis, triggered by synaptic activation of mGluR, can modify synaptic transmission (Huber et al. 2000).

4.2 Biochemical Activation

Activity-dependent modulation of synaptic strength in area CA I pyramidal cells is at least partially controlled by the balance between the activities of critical protein kinases and phosphatases in the postsynaptic cell, with the synaptic glutamate receptor being a potential substrate for this biochemical competition. In one model for the induction of LTP and LTD, during efferent activity, Ca²⁺ enters dendritic spines through NMDA receptors. High-frequency stimulation allows Ca²⁺ to reach high levels, which preferentially activates a protein kinase. Low-frequency stimulation allows Ca²⁺ to reach low levels, which preferentially activates a protein phosphatase. It is then argued that both the protein kinase and phosphatase act on a common synaptic phosphoprotein, the phosphorylation state of which controls synaptic strength (Bear and Malenka 1994).


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