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. 2008 Dec 23;6(12):2698-706.
doi: 10.1371/journal.pbio.0060318.

PKMzeta Maintains Spatial, Instrumental, and Classically Conditioned Long-Term Memories

Free PMC article

PKMzeta Maintains Spatial, Instrumental, and Classically Conditioned Long-Term Memories

Peter Serrano et al. PLoS Biol. .
Free PMC article


How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMzeta), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMzeta maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMzeta activity. We then examined, using ZIP, the effect of PKMzeta inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMzeta inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMzeta activity. Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMzeta inhibition in the BLA impaired retention of classical conditioned stimulus-unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMzeta inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMzeta activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.

Conflict of interest statement

Competing interests. The authors have declared that no competing interests exist.


Figure 1
Figure 1. Chelerythrine in DH Disrupts Place Avoidance Memory
Naive rats rapidly entered the shock zone on the first training trial but learned to avoid the location for several minutes by the eighth training trial. Chelerythrine (chel) or vehicle (veh) was injected in the DH 2 h before testing retention of 24-h memory. Chelerythrine, but not saline, eliminated retention of the memory, causing avoidance to drop to the level of when the rats were naive (F2,21 = 14.2; p = 0.0001; an asterisk (*) indicates p < 0.05, chel relative to veh). All data are presented as averages, with error bars indicating standard errors of the mean.
Figure 2
Figure 2. ZIP in DH Disrupts Spatial Memory
(A) Performance of the eight-arm radial maze task. Learning across 6 d (ten trials per day) was followed by a single retention trial after a 24-h interval. Two hours before the retention trial, each rat received a bilateral DH injection of either saline (sal, n = 9), the control peptide (scr-ZIP, n = 9), or ZIP (n = 8). The ZIP injection impaired overall performance ([A]; F 2,23 = 14.80; p = 10−5) by increasing reference memory errors ([C]; F 2,23 = 9.30; p = 0.001) without increasing working memory errors ([B]; F 2,23 = 1.16; p = 0.33). (D–G) Performance of the water maze task (D) during training (two four-trial blocks per day) and (E–G) during the unreinforced swim retention test after a 24-h interval. Each rat received a bilateral DH infusion of saline (n = 7), scr-ZIP (n = 7), or ZIP (n = 10) 2 h before the retention test. (E) Percent time in the target quadrant, (F) number of times the position of the escape platform was crossed, and (G) the color-coded time-in-location map for each treatment group during the retention trial. The same blue-to-red scale is used for each map, where the minimum time in the peak, red category is 0.9 s. ZIP impaired retention of spatial accuracy (F 2,21 = 3.96; p = 0.03), but not the spatial search procedure (F 2,21 = 2.08; p = 0.15). All data are presented as averages, with error bars indicating standard errors of the mean. An asterisk (*) indicates p < 0.05, ZIP relative to saline and scr-ZIP.
Figure 3
Figure 3. ZIP in BLA Disrupts Classically Conditioned Fear Memory
(A) Retention of context-conditioned fear 26 h after bilateral DH injection of saline (sal, n = 4), inactive (scr-ZIP, n = 7), or active ZIP (n = 6). ZIP did not impair retention of contextual fear (F 2,14 = 0.15; p = 0.86). (B) Retention of tone-conditioned fear after 22-h posttraining bilateral BLA injections. Retention was tested 2 h (sal, n = 6; scr-ZIP n = 3; ZIP n = 10) or 24 h (sal, n = 5; scr-ZIP n = 4; ZIP n = 8) after the injection. ZIP impaired retention of tone-conditioned fear (F 2,33 = 4.93; p = 0.01). (C) Immediate postshock freezing after bilateral BLA injections. Fear was tested 5 min (sal, n = 4; ZIP, n = 4) or 120 min (sal, n = 5; ZIP, n = 5) after the injections. ZIP did not affect immediate postshock freezing, indicating the expression of fear was intact (F 1,16 = 0.58; p = 0.46). All data are presented as averages, with error bars indicating standard errors of the mean.
Figure 4
Figure 4. ZIP in BLA Disrupts Inhibitory Avoidance Memory
Latency to enter the dark compartment during the acquisition and retention phases of inhibitory avoidance. Retention was tested 24 h after acquisition, 2 h after the bilateral BLA injections (sal, n = 7; scr-ZIP, n = 15; and ZIP, n = 16). The latency to enter the dark compartment was similar across groups during acquisition, but not during retention. The interaction between group and phase of the inhibitory avoidance task was significant (F 2,35 = 4.28; p = 0.02). ZIP impaired retention of inhibitory avoidance compared to the animals treated with saline and scr-ZIP, which were indistinguishable. The asterisk (*) indicates p < 0.01, ZIP relative to saline and scr-ZIP. All data are presented as averages, with error bars indicating standard errors of the mean.
Figure 5
Figure 5. Characterization of the Infusion Sites in the (A) DH and (B) BLA
Infusion sites from a subset of the animals are plotted on schematics of the brain at the indicated distance in millimeters posterior to bregma. The one third of the injection sites closest to the centroid location at each level fell within the black region. Two thirds fell within the medium-gray region, and all injections fell within the light-gray region.

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