Importantly, in our electrophysiological study, kif17−/− slices showed a deficit in L-LTP ( Figure 5I), a neuronal EGFR cancer event mimicking the in vivo process of memory consolidation. Thus, the impaired long-term memory of fear conditioning in kif17−/− mice may reflect an effect not only on the acquisition of memory, but also on processes related to consolidation. Consistently, further in vitro (

Figures 7A–7C) and in vivo (Figures 7D–7K and 8C–8F) experiments identified activity-dependent transcriptional control of the genes encoding KIF17 and NR2B by CREB. This could be the molecular basis underlying the impairment in the consolidation of long-term memory in kif17−/− mice. Based on these findings, it is considered that kif17−/− mice have defects in multiple phases of long-term memory formation. The level of KIF17/NR2B is increased in response to synaptic inputs. This process is mediated by CREB activation. A functional relationship between selleck chemicals llc KIF17/NR2B and CREB is suggested on the basis of the following evidence: (1) CREB activation was impaired in kif17−/− mouse neurons ( Figures 7A–7C). (2) Training for spatial memory formation upregulated KIF17, NR2B/2A, and pCREB in the hippocampus ( Figures 7D–7K). (3) Absence

of KIF17 blocked the upregulation of pCREB, NR2B, and NR2A induced by spatial memory tasks ( Figures 7D–7K). (4) Expression of a dominant-negative form of CREB suppressed kif17 and nr2b transcription and decreased the amount of NR2B ( Figures 8C–8F). (5) Expression of constitutively active CREB increased the levels of kif17 and nr2b transcription and increased the levels of KIF17 and NR2B. The NR2A level was also increased without alteration of nr2a transcription ( Figures 8C–8F). Our previous work provides further supporting evidence, namely, (6) the upstream promoter regions of kif17 and nr2b contain CREB binding sites,

and (7) overexpression of KIF17 resulted in an increase in the level of pCREB, concomitant with enhanced spatial memory ( Wong et al., nearly 2002). Taking all of these findings into account, it is suggested that the reciprocal enhancement of KIF17-mediated transport and CREB phosphorylation works in concert to fine-tune synaptic plasticity and thereby is important in memory formation (Figure 8G). In this scheme, KIF17 acts not only as a mediator for constitutive receptor transport, but also as a key player in the “augmented NR supply during memory formation” (Figure 8G). In brief, when synapses are activated, transcription of kif17 and nr2b is induced by CREB, resulting in an increase in the levels of KIF17 and NR2B. This increase leads to increased transport and further synaptic accumulation of NR2B. Conversely, in kif17−/− neurons, failure of the reciprocal regulation between KIF17/NR2B and CREB, as well as the accelerated degradation of NR2A mediated by the ubiquitin-proteasome system, could contribute to the memory disturbances found in kif17−/− mice.