Deficits in learning and memory are prominent features of many mental disorders. Understanding molecular mechanisms underlying learning and memory are key to the development of therapies to correct cognitive disorders in the treatment of mental illness. The goal of this study was to investigate the role for ERK5 MAP kinase and ERK5-regulated adult neurogenesis in the memory formation of contextual fear and the maintenance of this memory.
We previously reported that contextual fear memory is significantly reduced in ERK5 icKO mice at 24 h after animals were trained using a challenging training protocol (3×0.3 mA foot shocks) 
. Here, we demonstrate that under the same conditions, ERK5 icKO mice showed similar contextual fear memory as control mice when tested 2 min after training. Thus, the reduced contextual fear memory seen at 24 h using the 3×0.3 mA foot shocks training protocol is most likely due to a deficit in consolidation of the fear memory rather than deficits in memory acquisition and/or retrieval.
Since inhibition of adult neurogenesis may increase anxiety 
, it is possible that the deficits in remote contextual fear memory observed in ERK5 icKO mice may be due to increased anxiety. However, ERK5 icKO mice are not deficient in short-term (2 min, 1 day) contextual fear memory, nor in both short-term (1 day) and remote (5 wks, 15 wks, and 16 wks) cued fear memory. If increased anxiety significantly affects remote contextual fear memory, then it should have also affected short-term contextual and cued fear memory, as well as remote cued fear memory. Therefore, it seems unlikely that the observed defect of remote memory in ERK5 icKO mice is due to increased anxiety.
It is generally agreed that contextual fear memory is initially stored in the hippocampus for the short term. Furthermore, interaction between the hippocampus and neocortex after the formation of recent memory is crucial for the storage of remote memory regardless of the exact storage location for remote memory 
. Indeed, post-training deletion of erk5
, which reduces adult neurogenesis 
, during the hippocampus-dependent period (6 d post-training) caused retrograde amnesia of contextual fear memory. Together with a recent report using diphtheria toxin-based strategy to ablate mature, adult-generated neurons within the week after training 
, these data suggest that interference with adult neurogenesis can cause retrograde amnesia.
Whether the hippocampal formation is required for the maintenance of remote contextual memory once the memory is established is controversial 
. Furthermore, before this study, it was not known if continuing adult neurogenesis plays a role in the expression and maintenance of remote contextual memory. For example, one study suggests that adult neurogenesis modulates the duration of hippocampus-dependent period of associative fear memory but inhibition of adult neurogenesis does not cause loss or reduction of remote memory per se
. Using our transgenic mouse line, we were able to specifically and conditionally target erk5
in neural stem/progenitor cells in adult neurogenic regions, thus interfering with adult neurogenesis 
to assess the importance of adult-born neurons in the hippocampus for the expression and persistence of remote memory. Our data indicate a critical role for adult-born neurons in both the expression and maintenance of remote contextual memory using three different paradigms, exemplified with observed deficits when erk5
was conditionally deleted prior to training, 6 d after training, or 5 wks after training.
The cortex and basolateral amygdala are required for remote contextual fear memory 
. It is possible that the functional connectivity between the hippocampal formation and amygdala or cortex during memory retrieval and reconsolidation is important for the maintenance of remote contextual fear memory. Although this study does not directly address this functional connectivity, it is important to note that ERK5 is selectively expressed in the neurogenic regions but not other regions of the adult brain 
. Furthermore, the erk5
gene deletion is restricted to neurogenic regions of the adult brain 
. Data presented in this study clearly suggest that the continual formation of new neurons in the dentate gyrus is integral for the establishment and maintenance of remote contextual fear memory, even after the memory has transferred out of the hippocampus. Our data support the general hypothesis that the hippocampus has a long-term role in the continued expression of contextual fear memory 
, and may have important implications for the treatment of memory disorders.