BOX 2, cont'd (C) Acquisition of the delay eye-blink conditioned response (delay paired) and the unpaired condition (delay unpaired). (D) Total numbers of BrdU-labeled cells in the dentate gyrus of these animals following delay conditioning. These animals received BrdU injections 1 week before training and were perfused 24 hours after the last day of training. (n = 5-6). (E) Acquisition of place and cue learning in the Morris water maze. (F) Total numbers of BrdU-labeled cells in the dentate gyrus of these animals following spatial (place) or cue (cue) training. These animals received BrdU injections 1 week before training and were perfused 24 hours after the last day of training (n = 6). (G) Acquisition of the trace eye-blink conditioned response (trace paired) and the unpaired condition (trace unpaired) from animals injected with BrdU on the last day of training after all animals had reached learning criterion. These animals were perfused 24 hours after the BrdU injection. (H) Total numbers of BrdU-labeled cells in the dentate gyrus of these animals following trace conditioning (trace paired) (n = 5-6). Reproduced from Gould, Beylin, Tanapat, Reeves, and Shors (74).
have been identified so far, some interesting themes have begun to emerge.
It is notable that a prominent category of L-LTP-associated genes encode transcription factors (see Figure 5). One member of this category is one of the first L-LTP-associated genes identified: zif268 (aka krox24 and NGFI-A; see references 6, 11, 40-43). Zif268 encodes a transcription factor of the zinc finger family, and recent findings indicate that zif268 may be a target of the elk-1 transcription factor cascade (35). The zif268 homologue krox20, another zinc-finger transcription factor, is also regulated in L-LTP (44). The target genes regulated by zif268 and krox20 are still being worked out.
Zif268 is a member of the "immediate early gene" family of proteins, as are many of the L-LTP targets we will discuss such as BDNF, t-PA, and others. IEGs are rapid response, activity- and signal-regulated genes in a wide variety of cell types. Transcription factors of the fos/jun family are prototype IEGs, and a variety of early work has shown that fos and jun family members are also regulated in L-LTP. However, subsequent work has suggested that fos/jun regulation may be more of a general activity-related read-out as opposed to a specific signal associated with L-LTP. Nevertheless, fos/ jun signaling appears to be a likely component of the cascades set off by L-LTP-inducing stimulation, adding another example of transcription factor regulation to the list of gene targets in L-LTP.
An additional transcription factor worth noting in the context of secondary waves of transcription factor regulation is C/EBP. C/EBP is the CCAAT Enhancer Binding Protein, a known secondary target of CREB regulation in Aplysia sensory neurons. Cristina Alberini's lab has shown that the consolidation of mammalian long-term memory is associated with a relatively late (several hours post-training) elevation of C/EBP (45). While it is not known if this
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