Immediate early gene expression associated with the persistence of heterosynaptic long-term depression in the hippocampus.

Abstract

Long-term depression (LTD) of synaptic efficacy is likely to be as important in memory processing as the more well-known long-term potentiation (LTP). The case for LTD serving as a memory mechanism, however, requires that it be shown to persist across days or weeks at least. Here we examined the persistence of heterosynaptic LTD in the medial and lateral perforant path inputs to the dentate gyrus in awake rats and correlated this persistence with the degree of immediate early gene expression as assessed immunohistochemically. Rats were chronically implanted with separate stimulatIng electrodes in the medial and lateral perforant paths and an extraceilular field potential recording electrode in the dentate hilus. After recovery from surgery, either the medial or the lateral perforant path was tezed with 400-Hz trains, and homosynaptic LTP and heterosynaptic LTD were followed across time. Heterosynaptic LTD was shown to occur readily in awake animals and to persist across days or weeks, depending on the simulation protocol. The persistence of LTD and LTP was highly correlated within animals. Additional animals, given the same tetanization protocols, showed that the greatest immediate early gene expression occurred following that protocol which consistently gave the longest-lasting LTP and LTD.These data support the proposed role of LTD in memory processing but question whether immediate early genes are important for the persistence of LTP, LTD, or both.Information storage in the central nervous system is widely believed to occur as a result of changes in the efficacy of synaptic connections between neurons. Early observations of synaptic plasticity were made in the hippocampus, where long-term potentiation (LTP) of synapses in the dentate gyrus was induced by brief high-frequency stimulation of perforant path afferents from the entorhinal cortex (1, 2). LTP can last for many weeks, depending on the initial stimulation conditions (3), and a major question of interest is how the biochemical changes associated with LTP are maintained over time in the face of molecular turnover. One possibility involves altered gene expression. Support for this idea comes from recent demonstrations that a variety of postsynaptic genes, including immediate early genes (IEGs), respond rapidly to LTP-inducing stimuli (4-7). IEGs are of particular interest because many code for putative transcription factors and thus may participate in the biochemical cascade leading to genomically driven, lasting adaptations by neurons to afferent activity. We have shown that zif/268 and krox2O, and to a lesser extent c-jun,junB,junD, andfos-related genes, are preferentially expressed by stimulation patterns that generate LTP lasting weeks (LTP3) as opposed to days (LTP2) (7-9).Information storage may also involve weakening of synaptic efficacy, and indeed there are now many examples in the literature of long-term depression (LTD) of synapses in the hippocampus and elsewhere (10-12). One common form of LTD is heterosynaptic LTD, which occurs at q...

How long will long-term potentiation last?

“…Also, as for LTP, there may be important differences between NMDA receptor-dependent and receptor-independent LTD that have not yet been explored. By contrast, heterosynaptic LTD in the dentate gyrus lasts for as long as simultaneously induced LTP, and their decay rates are highly correlated (Abraham et al 1994). Whether LTD maintenance is as sensitive to behavioural variables as LTP is an important question that is currently under investigation.…”

Isolation rearing impairs wound healing and is associated with increased locomotion and decreased immediate early gene expression in the medial prefrontal cortex of juvenile rats

“…Our findings of decreased IEG expression in the mPFC in isolation reared rats during this developmental period are consistent with this finding in that both IEG expression (Lanahan and Worley 1998;Guzowski 2002) and dendrite spiny process development (Yuste and Bonhoeffer 2001) are measures of neuronal plasticity. Furthermore IEG expression has been linked to both long term potentiation (LTP) and long term depression (LTD) (Abraham, Christie et al 1994) and these processes (LTP and LTD) are associated with growth (Engert and Bonhoeffer 1999;Maletic-Savatic, Malinow et al 1999) and retraction (Zhou, Homma et al 2004) of spiny processes, respectively.…”

Fornix Lesions Decouple the Induction of Hippocampal Arc Transcription from Behavior But Not Plasticity

“…Stable memory-related synaptic modifications are dependent on both transcription and translation (Flexner et al, 1963;Montarolo et al, 1986;Frey et al, 1988). Protein synthesisindependent transcription of immediate-early genes (IEGs) is a key initial event required for the maintenance of memory and enduring synaptic changes (Abraham et al, 1994;Alberini et al, 1994;Morrow et al, 1999;Guzowski et al, 2000). Expression of the IEG Arc is necessary for certain forms of synaptic plasticity and memory consolidation (Guzowski et al, 2000).…”