Abstract SNACC-66

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Compensation by PKCι/λ when PKMζ is disabled results in abnormal and inefficient learning: Implications for Post-Operative Cognitive Dysfunction

Tsokas P, Hsieh C, Yao Y, Kass I, Sacktor T, Cottrell J
SUNY Downstate Medical Center, Brooklyn, NY, USA

Many studies have shown that the persistent kinase activity of PKMζ--a constitutively active, brain-specific isoform of the atypical PKC family of protein kinases--is crucial for late long-term potentiation (L-LTP) and long-term memory (LTM) maintenance. However, recent genetic evidence using constitutive null mutant mice lacking the PKCζ/PKMζ gene from conception has questioned this hypothesis. Here we show that the other member of the atypical PKC family, PKCι/λ, can compensate for PKMζ in the PKCζ/PKMζ null mouse, and that the null mutant mice display abnormal and inefficient learning. Furthermore, we find that similar to PKMζ, PKCι/λ expression remains elevated after L-LTP induction in the CA1 region, and for 24 hrs after training in specific layers of the dorsal hippocampus of mice. These results suggest a role of PKCι/λ in L-LTP and LTM, perhaps as a “back-up” mechanism when PKMζ is disabled in amnestic disorders. We have previously shown that sevoflurane anesthesia (2 hrs, 2 % Sevoflurane) results in an anatomically non-specific increase in PKMζ expression in the mouse hippocampus. This effect could introduce noise to the memory trace, resulting in post-operative cognitive dysfunction. Our ongoing research also examines the possible involvement of the other atypical PKC, PKCι/λ, in post-operative cognitive dysfunction.

Methods:

Behavior: Adult mice received active place avoidance training; test at 24 hrs.
Immunoblots: PKMζ, PKCι/λ, actin.
Immunohistochemistry: Coronal sections; PKMζ and PKCι/λ; laser confocal microscopy.
L-LTP: induced in CA3-CA1 synapses of acute hippocampal slices.
Post-synaptic perfusion of PKCι/λ via whole-cell patch clamp.

Results:

The increase in PKCι/λ levels in the hippocampus relative to untrained controls was 149 +/- 9 % for trained animals (n = 8, p < 0.05) compared to 100 +/- 9 % for control animals (n = 8). The trained group also showed robust PKCι/λ increases in the dendrites of strata oriens, radiatum and lacunosum moleculare of the CA1 region, as well as in the molecular layer and the hilus of the dentate gyrus (DG). No significant changes were seen in the stratum pyramidale of CA1 and the granule cell layer of the DG.
Similar to PKMζ, postsynaptic perfusion of PKCι/λ potentiated postsynaptic AMPAR responses in CA1 pyramidal cells in hippocampal slices, and this effect was blocked by 5 μM ZIP (n’s = 4, F2,9 = 31.76, P < 0.01; PKCι/λ vs. baseline, P < 0.01; PKCι/λ vs. ZIP/PKCι/λ, P < 0.01; ZIP/PKCι/λ vs. baseline, P = 0.93). ZIP inhibition was less potent for PKCι/λ, than for PKMζ.

Conclusion:

L-LTP induction and LTM consolidation are associated with increases in PKCι/λ protein in specific layers of the dorsal hippocampus. Post-synaptic perfusion of PKCι/λ in pyramidal CA1 neurons is sufficient to produce L-LTP. These results suggest a role for the kinase in the encoding of a spatial memory (engram) in the hippocampus, perhaps as a “back-up” mechanism to PKMζ. Further work will be required to determine whether sevoflurane anesthesia has similar effects on PKCι/λ expression in the hippocampus, as it does on PKMζ, thereby introducing “noise” in the engram that could account for post-operative cognitive dysfunction.


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