Emerging evidence of insulin-like growth factor 2 as a memory enhancer: a unique animal model of cognitive dysfunction with impaired adult neurogenesis

Abstract

In the current aging society, cognitive dysfunction is one of the most serious issues that should be urgently resolved. It also affects a wide range of age groups harboring neurological and psychiatric disorders, such as Alzheimer's disease and schizophrenia. Although the molecular mechanism of memory impairment still remains to be determined, neuronal loss and dysfunction has been revealed to mainly attribute to its pathology. The discovery of neural stem cells in the adult brain that are proliferating and able to generate functional neurons has given rise to the idea that neuronal loss could be rescued by manipulating endogenous neural progenitor and stem cells. To this end, we must characterize them in detail and their developmental programming must be better understood. A growing body of evidence has indicated that insulin-like peptides are involved in learning and memory and maintenance of neural progenitor and stem cells, and clinical trials of insulin as a memory enhancer have begun. In contrast to the expectation of insulin and IGF1, the roles of IGF2 in cognitive ability have been poorly understood. However, recent evidence demonstrated in rodents suggests that IGF2 may play a pivotal role in adult neurogenesis and cognitive function. Here, we would like to review the rapidly growing world of IGF2 in cognitive neuroscience and introduce the evidence that its deficit is indeed involved in the impairment of the hippocampal neurogenesis and cognitive dysfunction in the model mouse of 22q11.2 deletion syndrome, which deletes Dgcr8, a critical gene for microRNA processing.

Altered insulin-like growth factor-2 signaling is associated with psychopathology and cognitive deficits in patients with schizophrenia

“…Our present study shows that schizophrenia patients displayed poorer performance in processing speed, working memory, attention, visual memory, and executive function than the normal controls, identical to previous studies [30,36]. IGF-2 has been strongly linked to cognition in the last decades [37]. Specifically, the ApaI polymorphism of the IGF-2 gene was associated with the general cognition and selective attention index in healthy individuals [21].…”

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

“…Moreover, MAPK signaling has been associated with circadian aspects of hippocampal memory formation, although the upstream mechanisms have not yet been identified so far (15). In addition, IGF2 signaling has been associated with memory consolidation and extinction of fear memory in the hippocampus (34,43,44). Our analysis reveals an additional role for IGF2/MAPK signaling in cortex-dependent cognitive processing.…”

“…An associated reduction of MAPK activity in Igf1R/InsR CaMKII-cre compared with Igf1R/InsR fl/fl mice, however, was restricted to the ACx and could not be observed in the Hi. Therefore, it seems likely that IGF2 signaling uses regionally different modes of action using both the IGF1R/INSR and IGF2R to activate MAPK in a context-dependent way (34,43,44,47). The significance of MAPK activity for the timing of memory formation in the hippocampus has been addressed already in a circadian context (15,17,41) and the disruption of clock genes leads to a memory impairment (48)(49)(50)(51).…”

Long days enhance recognition memory and increase insulin-like growth factor 2 in the hippocampus

“…The effects of light on memory in the current study are likely due to the alteration of hippocampal clock function that changes the daily regulation of IGF2. Because IGF2 signaling has been linked to MAPK signaling 48, 49 , this highlights new areas for future research investigating the molecular links between circadian and cognitive function.…”