Review
Long-term depression: multiple forms and implications for brain function

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Long-term potentiation (LTP) and long-term depression (LTD) remain widely accepted vertebrate models for the cellular and molecular mechanisms that underlie synaptic changes during learning and memory. Although LTD is a phenomenon that occurs in many regions of the CNS, it is clear that the mechanisms recruited in its induction and expression can vary, depending on many factors, including brain region and developmental time point. LTD in the hippocampus and cerebellum is probably the best characterized, although there are also other brain areas where mechanisms of LTD are well understood, and where it is thought to have a functional role.

Introduction

Efforts to understand synaptic plasticity are driven by the belief that such synaptic modifications might occur during learning and memory. However, it is extremely difficult to demonstrate directly that learning-induced synaptic changes occur following experience. Just one consideration is that these synaptic changes could be sparsely encoded and that the use of population measures to detect such changes might prove inadequate. However, even knowing whether such a change is associated with learning and memory cannot prove that learning is caused by such changes. Therefore, ultimately, it is desirable to know whether long-term depression (LTD) really has a specific independent role in learning and memory, or if it serves as an adjunct to long-term potentiation (LTP) – for example, by enhancing signal-to-noise ratio, renormalizing synaptic weights after LTP has occurred or deleting previously stored information.

LTD can be classified with regard to the ‘learning rule’ that it follows [1]. Homosynaptic LTD conforms to the Hebbian requirement of simultaneous pre- and postsynaptic activity [2], and included under this classification is associative LTD, which is also homosynaptic but with the difference that the requisite postsynaptic activity is provided by neighbouring, converging afferents activated either in conjunction or in alternation with a second afferent input. However, heterosynaptic LTD occurs at a synapse in which the presynaptic input remains inactive, and postsynaptic activity is driven by other converging afferents. This was, in fact, the first form of LTD to be discovered in the hippocampus when LTP-inducing stimuli delivered to one pathway were found to elicit heterosynaptic LTD in a separate, unstimulated pathway 3, 4. This last form of plasticity is peculiar to LTD because LTP does not occur in the absence of presynaptic activity, and, as such, this form of LTD does not obey the classical Hebb rule and is often referred to as ‘anti-Hebbian’. The discovery of heterosynaptic LTD in CA1 of hippocampal slices [3] and the dentate gyrus in vivo [4] was then followed by the first demonstration of homosynaptic depression, in which established LTP was effectively reversed with low-frequency stimulation (LFS; 1–5 Hz) [5]. This form of LTD, known as depotentiation, is thought to be distinct from de novo LTD and is a potentially important form of plasticity.

From observations of ocular dominance in the developing visual cortex Bienenstock et al. [6] developed a theory to account for bidirectional synaptic modification by positing a ‘modification threshold’ based on the level of postsynaptic activation. From this model, uncorrelated pre- and postsynaptic activity, as would occur in monocular deprivation, results in LTD. This model stimulated the search for input-specific de novo homosynaptic LTD, subsequently demonstrated at CA1–Schaffer collateral synapses in hippocampal slices (CA1-LTD) 7, 8 and in visual cortex slices [9].

Section snippets

Mechanisms of LTD: induction

Glutamatergic transmission is mediated by ionotropic and metabotropic classes of glutamate receptor. Ionotropic glutamate receptors are subdivided into three groups: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainate receptors [10]. Metabotropic glutamate (mGlu) receptors are divided into eight known subtypes (mGlu receptors 1–8) and three groups based on sequence homology, second messenger coupling and pharmacology 10, 11.

The stimulation

Developmental regulation of LTD

Significantly, homosynaptic LTD is developmentally downregulated in the rat hippocampus [19]. Standard LFS (900 stimuli; 1 Hz), normally sufficient to induce LTD in juvenile rat hippocampus, is not effective in the adult unless conditions are manipulated pharmacologically or the stimulus protocol modified [20]. The processes underlying this developmental plasticity change remain to be established but it is plausible that NMDA receptor subunit composition and/or location might have a role 21, 22.

Mechanisms of LTD: expression

This topic has been the subject of several recent reviews 33, 34, 35 and will therefore only be touched upon here. NMDA receptor-dependent LTD is thought to be predominantly expressed postsynaptically through changes in AMPA receptor properties. One such change in LTD is dephosphorylation of Ser845 on the C-terminal of the GluR1 subunit of AMPA receptors. This alteration is primarily thought to decrease open channel probability and thereby reduce AMPA receptor-mediated transmission. In

A physiological role for hippocampal LTD?

In humans, bilateral damage to the hippocampus results in anterograde amnesia, suggesting that it deals with the acquisition of new information, whereas long-term memories are stored elsewhere. In humans, monkeys and rats damage to the hippocampus or its major connections, such as the fornix, also leads to impairment in the performance of tasks necessitating the use of spatial information. It is thought that what relates the role of the hippocampus in spatial and nonspatial processing is the

Cerebellar LTD

The cerebellum is crucial for vertebrate motor learning of finely calibrated movement and reflexes. Its elaborate, repetitive and modular structural organization has attracted interest in its role in motor learning and how such information might be stored in this structure. Inhibitory Purkinje cells (PCs) provide the sole cerebellar output pathway, projecting to vestibular and deep cerebellar nuclei to drive specific movements. PCs have two types of excitatory input. The first, and predominant,

Striatal LTD

The striatum of the basal ganglia is involved in motor learning. On the basis of connectional and functional differences, it is divided into two subregions: the dorsal striatum and nucleus accumbens (NAc) of the ventral striatum. Functionally, the dorsal striatum has a role in the production of task-oriented motor sequences and habit learning, whereas the NAc (which, together with the ventral tegmental area, forms part of the mesolimbic dopamine system) is involved in working memory, in the

Visual cortex

LTD in the visual cortex is well characterized and might subserve the development of ocular dominance. Temporary deprivation of visual stimulation to an eye during a crucial period of postnatal development leads to loss of responsiveness to further visual stimuli. Lending support to the Bienenstock–Cooper–Munro model [6], LFS produces LTD in layers 2–3 of visual cortex slices in a similar way to that observed in CA1, requiring postsynaptic NMDA receptor activation and protein phosphatase

Perirhinal cortex

The perirhinal cortex is a high-order, multimodal region situated within the temporal lobe, lateral to the hippocampal formation and medial to area temporal cortex (TE) (visual and auditory processing). The perirhinal cortex and adjacent area are essential for a variety of different types of learning, including paired-associate learning, contextual fear conditioning, and both the familiarity discrimination (judgements concerning whether an object has been seen previously) and object

Concluding remarks

We have discussed the mechanisms of LTD in a variety of brain regions. In addition, whether the mechanisms underlying LTD have any role in the normal physiological functions of that brain region have been explored.

There have been recent advances in the understanding of mechanisms of LTD, such as the involvement of different NMDA receptor subtypes, the role of cannabinoids and the role of physiological stress in promoting the induction of LTD. All of these advances, and others, are crucially

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