Genes whose products are induced in response to extracellular stimulation with a delay of a few hours

Similarly to "immediate early genes, late response genes (or simply 'late genes') is a term born in virology (Honess and Roizman 1974; Weinheimer and McKnight 1987). In mammalian cells, the expression of immediate early genes is detectable within minutes of stimulation, followed by the expression of delayed early genes, and finally, starting a few hours after stimulation, late response genes (Nathans et al. 1988;Lanahan et al. 1992). The latter encode a variety of proteins, including transcription factors,1 enzymes that produce other cellular products (biosynthetic enzymes), enzymes that degrade other proteins (proteases), and cytoskeletal elements.

The role of the late response genes in learning and memory is commonly construed within the prevailing conceptual framework, which describes "consolidation of long-term memory as involving "synaptic remodelling and growth (Goelet et al. 1986; Dudai 1989; Milner et al.

1998; "development). Only little, however, is currently known about the identity of the late genes that are supposed to subserve these postulated remodelling and growth processes. The problem is that, whereas the careful analysis of the pattern of gene expression during the first hours and days after a training experience is likely to reveal many changes, determining the relevance of these changes to learning and memory is a tricky business.

Here are a few examples of genes whose modulated expression following training lags after that of the immediate early genes. In "Aplysia, BiP/GRP78, an endoplasmic-reticulum resident protein involved in folding and assembly of newly synthesized proteins (a type of protein termed 'chaperon'), was found to be synthesized in neurons 3 hours after the onset of long-term facilitation, which is considered the cellular analogue of long-term "sensitization (Kuhl et al. 1992). This fits the time course expected of a delayed early gene product. In the same "system, calreticulin, a major "calcium-binding protein in the endoplasmic reticulum, also displayed a delayed time course of post-training expression (Kennedy et al. 1992). In the mammalian brain, 24 hours after the induction of "LTP in the rat "hippocampus, a transient increase was observed in the expression of the messenger RNA (mRNA) of ERK-2 and raf-B, two components of a major "intracellular signal transduction cascade (Thomas et al. 1994). Two gene products with the kinetics of late genes were also reported to increase transiently in the rat hippocampus after water "maze training (Cavallaro et al. 1997). One of these genes encodes the enzyme glutamate dehydro-genase (mRNA peaking at 6 h post-training), the other a ryanodine "receptor (an intracellular "ion channel involved in "homeostasis of cellular calcium; its mRNA peaked at 6-12 hours post-training).

Although it is rather straightforward to try and incorporate the aforementioned findings and the like into "models of synaptic "plasticity and neuronal remodelling, the truth is that the real function of the identified late genes in consolidation and memory is yet unclear. Do their products fulfil a causal role in altering the "internal representations in the neuronal circuits that encode memory? Are they ultimately stabilizing or augmenting the molecular machinery that is altered in the short term, e.g. post-translationally modified ion channels, enzymes (e.g. "protein kinase), or receptors? Are they required for growth processes to supply active neurons with sufficient synaptic space for future computations? Or, alternatively, are they only manifestations of homeostatic processes that provide "nutrients and restore function to the exhausted, stressed cells?

In some potential scenarios, the expression of the late genes could be transient, whereas in others, the cell could commit itself to expressing these genes differently from the time of consolidation on. The distinction between transient and lasting modulation reflects on the candidate role(s) of the late gene products in the cellular machinery of learning. If the modulation of the expression of the late response genes is only transient, the products of these genes could function as cellular switches that trigger the shift of the cell from one stable state to another, but not as storage or "retrieval devices. In contrast, if the expression of these genes itself switches into a different lasting state, this implies that the products of the late genes could be storage or readout components in the neuronal machinery of memory.

The investigation of identified neurons in identified circuits that subserve identified behaviours, e.g. in Aplysia, offers significant advantages in the search for the concrete role of late response genes in the formation of persistent memories. The fast developments in molecular neurobiology ensures that pretty soon, relevant information will become available from in situ analysis of identified circuits in the brain of behaving mammals, which learn, for example, to avoid a taste ("conditioned taste aversion), fear a tone ("fear conditioning), or navigate in space ("hippocampus).

Selected associations: Consolidation, Development, Immediate early genes, Phase, Protein synthesis

1For what transcription factors are, see *CREB and 'immediate early genes.

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