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PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA - PLoS Biol. (2008)

Bottom Line: Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Brooklyn, New York, USA.

ABSTRACT
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.

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ZIP in BLA Disrupts Inhibitory Avoidance MemoryLatency 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 (F2,35 = 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.
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pbio-0060318-g004: ZIP in BLA Disrupts Inhibitory Avoidance MemoryLatency 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 (F2,35 = 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.

Mentions: We then tested whether other forms of memory that depend on the BLA also require persistent PKMζ activity for maintenance. Injecting ZIP into the BLA 22 h after inhibitory avoidance conditioning impaired retention of the conditioned response that was tested 2 h later (Figure 4; p < 0.01). Two weeks later, the impairment persisted (latency to enter the dark compartment: n's = 4; scr-ZIP = 297 ± 104 s; ZIP = 79 ± 50 s; t7 = 2.5; one-tailed p < 0.05). Thus, long-term memories for both classically conditioned fear and instrumentally conditioned inhibitory avoidance depend upon persistent PKMζ activity in the BLA.


PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories.

Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA - PLoS Biol. (2008)

ZIP in BLA Disrupts Inhibitory Avoidance MemoryLatency 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 (F2,35 = 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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2605920&req=5

pbio-0060318-g004: ZIP in BLA Disrupts Inhibitory Avoidance MemoryLatency 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 (F2,35 = 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.
Mentions: We then tested whether other forms of memory that depend on the BLA also require persistent PKMζ activity for maintenance. Injecting ZIP into the BLA 22 h after inhibitory avoidance conditioning impaired retention of the conditioned response that was tested 2 h later (Figure 4; p < 0.01). Two weeks later, the impairment persisted (latency to enter the dark compartment: n's = 4; scr-ZIP = 297 ± 104 s; ZIP = 79 ± 50 s; t7 = 2.5; one-tailed p < 0.05). Thus, long-term memories for both classically conditioned fear and instrumentally conditioned inhibitory avoidance depend upon persistent PKMζ activity in the BLA.

Bottom Line: Similarly, PKMzeta inhibition in the hippocampus did not affect contextual information after fear conditioning.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Brooklyn, New York, USA.

ABSTRACT
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.

Show MeSH