Functional loss of PKMζ in the dorsal hippocampus potentiates the time-dependent increase in false contextual fear memory and impairs spatial recognition memory in mice

Introduction False contextual fear memory has been attributed to a time-dependent loss of precision in contextual memory representations. In this study, we investigated the role of protein kinase M zeta (PKMζ), a key molecule in the maintenance of hippocampus-dependent long-term memory, in false contextual fear memory within the dorsal (dHPC) and ventral hippocampus (vHPC). Methods Two weeks prior to behavioral testing, male C57BL/6J mice (7–10 weeks old) received bilateral injections of adeno-associated virus (AAV PHP.eB) into the dHPC or vHPC to induce PKMζ knockdown (PKMζ KD), overexpression of wild-type PKMζ (PKMζ WT), or kinase-inactive PKMζ (PKMζ K281R). False contextual fear memory was assessed by measuring freezing behavior in Context B at 3 and 24 h following exposure to Context A with or without unconditioned stimulus presentation [US(+) and US(−), respectively]. Spatial recognition memory was evaluated using the two-trial novel arm recognition test in the Y-maze. Results As shown in our previous work, mice exhibited freezing in Context B after receiving a US in Context A, whereas mice that did not receive such a stimulus showed minimal freezing. These data confirmed that freezing in Context B reflects false contextual fear memory. False fear responses were evident at 3 h and were further increased at 24 h. Freezing at 24 h was markedly enhanced in dHPC PKMζ knockdown mice compared with that in AAV control-injected mice. PKMζ WT overexpression prevented the increase in freezing at 24 h, whereas PKMζ K281R overexpression mimicked the effects of PKMζ KD. Furthermore, PKMζ knockdown in the dHPC impaired spatial recognition memory, indicating that hippocampus-dependent spatial processing was disrupted. In contrast, PKMζ manipulation in the vHPC did not affect false contextual fear memory but did impair spatial recognition memory. Discussion These findings are consistent with the possibility that functional loss of PKMζ in the dHPC affects contextual memory processes in a manner that may contribute to the time-dependent increase in false contextual fear and impaired spatial recognition memory.