Reduced Adult Hippocampal Neurogenesis and Working Memory Deficits in theDgcr8-Deficient Mouse Model of 22q11.2 Deletion-Associated Schizophrenia Can Be Rescued by IGF2

Abstract

DiGeorge syndrome chromosomal region 8 (Dgcr8), a candidate gene for 22q11.2 deletion-associated schizophrenia, encodes an essential component for microRNA (miRNA) biosynthesis that plays a pivotal role in hippocampal learning and memory. Adult neurogenesis is known to be important in hippocampus-dependent memory, but the role and molecular mechanisms of adult neurogenesis in schizophrenia remain unclear. Here, we show that Dgcr8 heterozygosity in mice leads to reduced cell proliferation and neurogenesis in adult hippocampus, as well as impaired hippocampus-dependent learning. Several schizophrenia-associated genes were downregulated in the hippocampus of Dgcr8 ϩ/Ϫ mice, and one of them, insulin-like growth factor 2 (Igf2), rescued the proliferation of adult neural stem cells both in vitro and in vivo. Furthermore, IGF2 improved the spatial working memory deficits in Dgcr8 ϩ/Ϫ mice. These data suggest that defective adult neurogenesis contributes to the cognitive impairment observed in 22q11.2 deletion-associated schizophrenia and could be rectified by IGF2.

The effect of insulin and insulin-like growth factors on hippocampus- and amygdala-dependent long-term memory formation

“…IGF2, like IGF1 and insulin, may also be beneficial in rescuing cognitive impairments in diseases, as it can promote synapse formation and spine maturation in the mouse brain (Schmeisser et al 2012), and perhaps through the IGF1receptor (IGF1R), may affect neurogenesis and consequently contribute to hippocampaldependent spatial learning and memory (Bracko et al 2012;Ouchi et al 2013). Like IGF1 and insulin, the expression of IGF2 and IGF2 receptor (IGF2R) have been found altered in the brain AD patients (Kar et al 2006) and IGF2 ameliorates AD-related deficits in an AD mouse model (Mellott et al 2014).…”

Unlocking epigenetic codes in neurogenesis

“…Interestingly, many of the abnormal neurons are actually produced postnatally, indicating a role for Dicer in the transition of active embryonic RGs to the quiescent adult form (Nowakowski et al 2013). In addition, both Drosha and AGO2 may also regulate neurogenesis (Pepper et al 2009;Knuckles et al 2012;Ouchi et al 2013). Moreover, other miRNA biogenesis regulators are found to be involved in the modulation of neurogenesis.…”

Adult Neurogenesis and Psychiatric Disorders

“…The 22q11.2 microdeletion is the most commonly occurring copy number variation (CVN) (Botto et al 2003) and is a well-established risk factor for schizophrenia (Pulver et al 1994;Murphy et al 1999). Heterozygote Dgcr8 knockout mice (Dgcr8 þ/2 ) show a significant decrease in the proliferation of adult hippocampal neural progenitor cells and corresponding deficits in spatial working memory (Stark et al 2008;Ouchi et al 2013). Interestingly, rescue of decreased proliferation in adult hippocampus by administration of insulin-like growth factor (IGF)-2 was sufficient to reverse the behavioral defects in hippocampal-dependent learning, suggesting a potential role of defective adult hippocampal neurogenesis in mediating deficits in learning observed in schizophrenia patients.…”