Protein kinase M ζ (PKMζ) is a constitutively active form of atypical PKC that is exclusively expressed in the brain and implicated in the maintenance of long-term memory1–9. Most studies that support a role for PKMζ in memory maintenance have used pharmacological PKMζ inhibitors such as the myristoylated zeta inhibitory peptide (ZIP) or chelerythrine. Here, we used a genetic approach and targeted exon 9 of the Prkcz gene to generate mice that lack both protein kinase C ζ (PKCζ) and PKMζ (Prkcz−/− mice). Prkcz−/− mice showed normal behavior in a cage environment and in baseline tests of motor function and sensory perception, but displayed reduced anxiety-like behavior. Surprisingly, they did not show deficits in learning or memory in tests of cued fear conditioning, novel object recognition, object location recognition, conditioned place preference (CPP) for cocaine, or motor learning, when compared with wild-type littermates. ZIP injection into the nucleus accumbens (NAc) reduced expression of cocaine CPP in Prkcz−/− mice. In vitro, ZIP and scrambled ZIP inhibited PKMζ, PKCι and PKCζ with similar Ki values. Chelerythrine was a weak inhibitor of PKMζ (Ki = 76 µM). Our findings show that absence of PKMζ does not impair learning and memory in mice, and that ZIP can erase reward memory even when PKMζ is not present.

The spatial receptive fields of neurons in medial entorhinal cortex layer II (MECII) and in the hippocampus suggest general and environment-specific maps of space, respectively. However, the relationship between these receptive fields remains unclear. We reversibly manipulated the activity of MECII neurons via chemogenetic receptors and compared the changes in downstream hippocampal place cells to those of neurons in MEC. Depolarization of MECII impaired spatial memory and elicited drastic changes in CA1 place cells in a familiar environment, similar to those seen during remapping between distinct environments, while hyperpolarization did not. In contrast, both manipulations altered the firing rate of MEC neurons without changing their firing locations. Interestingly, only depolarization caused significant changes in the relative firing rates of individual grid fields, reconfiguring the spatial input from MEC. This suggests a novel mechanism of hippocampal remapping whereby rate changes in MEC neurons lead to locational changes of hippocampal place fields.

There is substantial evidence implicating N-methyl-d-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia since morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR−/−) mouse in which the first coding exon of the mouse serine racemase gene has been deleted, to explore the role of d-serine in regulating cognitive functions as well as dendritic architecture. SR −/− mice exhibited a significantly disrupted representation of the order of events in distinct experiences as revealed by object recognition and odor sequence tests; however, SR −/− animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR −/− mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR−/− mice displayed reductions in the complexity, total length, and spine density of apical dendrites. These findings demonstrate that d-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the mPFC. Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.