Analyses of improved long term memory in SHARP1 and SHARP2 double knockout mice

Abstract

The transition of recent experiences into stable and remote memory traces is an important task that mainly occurs during sleep. Sleep-associated consolidation of remote long-term memory is based on cortical networks that are concerted by the prefrontal cortex. The bHLH transcription factors SHARP1 and SHARP2, modulators of the circadian system, are expressed mainly in the hippocampus and cortex of the mammalian brain and are partially redundant in function. SHARP1/DEC2 has been shown to control sleep length and increased vigilance during wake in humans as well as in mice. We hypothesized that these factors could be involved in cortex dependent memory consolidation. Therefore, we investigated the role of SHARP1 and SHARP2 in cognitive processing. In order to study prefrontal cortex-associated cognitive performance, we studied remote memory and flexible learning of Sharp1 and Sharp2 single and double mutant mice. Sharp1 and Sharp2 double mutant mice (S1/2-/-) showed enhanced anterior cortex (ACx) dependent remote fear memory formation as well as improved reversal learning, but did not display alterations in hippocampus (Hi) dependent recent fear memory formation. In contrast single mutants did not display any learning or memory phenotype. In line, molecular and biochemical analyses revealed elevated IGF2 signaling, p44/42-MAPK and S6 activity in the ACx but not the Hi of S1/2-/- mice. We did not observe similar changes in single mutant mice. In order to study the effect of IGF2 on cognitive processes, we studied the function of its target receptors in the brain, the insulin receptor (INSR) and IGF1 receptor (IGF1R). The analysis of forebrain specfic null mutants of the INSR and IGF1R revealed their implication in memory formation. Mice lacking both receptors in CaMKII positive neurons in the Hi and cortex exhibited a significantly reduced fear memory. Furthermore, AAV2 virus mediated IGF2 over-expression in the ACC enhanced remote fear memory formation. In summary, we conclude that the bHLH transcription factors SHARP1 and SHARP2 are involved in cognitive processing by controlling Igf2 expression and associated signaling xvii xviii ABSTRACT cascades. In parallel studies performed with aged S1/2-/- mice revealed reduced life span together with an overall loss of contextual fear memory. More specific, recent memory was significantly lower compared to WT and remote memory was attenuated to the level of the control mice. To exclude that memory enhancement via insulin signaling might trigger aging related processes, further studies are needed. Overall, our analyses provide evidence that the control of sleep and memory consolidation may share common molecular mechanisms.