PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI: http://dx.doi.org/10.7554/eLife.14846.001

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase’s action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1 day to 1 month after training. Therefore, if the mechanisms of PKMζ’s persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1 day to 1 month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase’s action during long-term and remote spatial memory maintenance.

1. The effect of sodium influx on anoxic damage was investigated in rat hippocampal slices.Previous experiments demonstrated that a concentration of tetrodotoxin which blocks neuronal transmission protects against anoxic damage. In this study we examined low concentrations of lidocaine (lignocaine; which do not block neuronal transmission), for their effect on recovery of the evoked population spike recorded from the CAl pyramidal cell layer. 2. Recovery of the population spike, measured 60 min after a 5 min anoxic period, was 4 + 2% of its preanoxic, predrug level. Lidocaine concentrations of 10, 50, and 100 /M significantly improved recovery to 56 + 12, 80 + 7 and 70 + 14 %, respectively. 3. Lidocaine (10 /M) did not alter the size of the evoked response before anoxia and had no significant effect on potassium levels or calcium influx during anoxia. It did, however, reduce cellular sodium levels (146 + 7 vs. 202 + 12 nmol mg-) and preserve ATP levels (2-17 + 0 07 vs. 1-78 + 0 07 nmol mg-1) during anoxia. All values were measured at the end of 5 min of anoxia except those for Ca2+ influx which were measured during 10 min of anoxia. 4. High concentrations of lidocaine (100 /M) did not improve recovery significantly over that observed with 10 jtM. They also had no significantly greater effects on sodium levels than 10/SM lidocaine (137 ± 12 vs. 146 + 7 nmol mg-); however, 100 /M lidocaine significantly improved potassium (202 + 18 vs. 145 + 6 nmol mg-1) and ATP (2-57 + 0-06 vs. 2-17 + 0 07 nmol mg-') levels, while reducing calcium influx (7-76 + 0-12 vs. 9X24 + 0 39 nmol mg-1 (10 min)-1) when compared with 10 /M lidocaine. 5. We conclude that sodium influx and ATP depletion are of major importance in anoxic damage since 10 uM lidocaine reduced these changes during anoxia and improved recovery of the population spike. In addition, our results indicate that the properties of the sodium channel are altered during anoxia, since sodium influx is blocked by a concentration of lidocaine that does not affect the population spike in the preanoxic period.Reduced oxygen delivery to the brain can lead to permanent loss of brain function (Hansen, 1985;Siesjo, 1988). It is important to understand the mechanism of this damage if one is to protect neurons. Studies have implicated calcium