br Introduction Newborn neurons are continuously generated t

Introduction Newborn neurons are continuously generated throughout life in several areas of the mammalian brain, including the subgranular zone (SGZ) of the hippocampal dentate gyrus (Imayoshi et al., 2008; Palmer et al., 1997; Zhao et al., 2008). Adult hippocampal neurogenesis is essential for neuronal addition and hippocampal growth, potentially contributing to new memory formation during adulthood (Deng et al., 2010; Dupret et al., 2007; Imayoshi et al., 2008; Sahay et al., 2011; Saxe et al., 2006). Adult neural precursor ubiquitin conjugating enzyme (NPCs) in the SGZ predominantly give rise to transit-amplifying cells and neuroblasts, which ultimately generate granule neurons in the hippocampal dentate gyrus (Ming and Song, 2011; Toni et al., 2008; Wang et al., 2012; Zhao et al., 2008). An early and dramatic decline in hippocampal neurogenesis that occurs in mice during early adulthood (3–6 months) is associated with a reduction in neural progenitor proliferation and newborn neuron survival (Kuipers et al., 2015). In contrast, the rate of neuronal differentiation is constant during early adulthood and remains sustained even in older (1–1.5 years old) mice (Kuipers et al., 2015). Disruption of this ongoing neurogenesis has been proposed to play a role in progressive neurodegenerative disorders such as Alzheimer\'s disease (Mu and Gage, 2011; Winner et al., 2011; Zhao et al., 2008). Therefore, understanding the underlying molecular mechanisms that sustain the age-dependent hippocampal neurogenesis will provide a fundamental basis to elucidate the pathogenesis and therapeutic targets of Alzheimer\'s disease. We previously showed that an atypical protein kinase C-CREB binding protein (aPKC-CBP) pathway is important for the differentiation of embryonic NPCs into all three neural cell lineages: neurons, astrocytes, and oligodendrocytes (Wang et al., 2010). Specifically, we demonstrated that activation of aPKC leads to Ser436 phosphorylation in CBP, a histone acetyltransferase, and that this phosphorylation causes transcription of genes that are associated with the three cell lineages. Moreover, we demonstrated that metformin, an AMP kinase (AMPK) activator, could activate the aPKC-CBP pathway to promote neurogenesis and enhance spatial memory formation in adult mice (Wang et al., 2012; Fatt et al., 2015). Interestingly, another recent study demonstrated that CBP is required for enriched environment-induced adult hippocampal neurogenesis and learning and memory (Lopez-Atalaya et al., 2011). Together, these findings suggest that CBP-mediated epigenetic regulation plays a central role in integrating environmental/microenvironmental changes to the determination of NPC differentiation in the developing and adult brain. The specificity of CBP actions is determined by its transcription factor binding partners. One of the binding partners is CREB (cyclic AMP response element binding protein), which is known to play a central role in regulating hippocampal plasticity, neurogenesis, and memory formation (Merz et al., 2011; Mizuno et al., 2002; Nakagawa et al., 2002a; Silva et al., 1998). When CREB is phosphorylated at Ser133, it recruits CBP and positively regulates CREB-mediated gene transcription (Parker et al., 1996; Shih et al., 1996). Intriguingly, the phosphorylated CREB at Ser133 (pS133-CREB) is stably expressed in doublecortin (DCX)-positive neuroblasts/newborn neurons in the hippocampal SGZ, suggesting its central role in neuronal differentiation and/or maturation (Merz et al., 2011). Moreover, previous work in liver cells has shown that aPKC-dependent Ser436 phosphorylation of CBP can regulate its association with CREB (He et al., 2009). These findings led us to test the hypothesis that activation of the aPKC-CBP pathway may modulate hippocampal neurogenesis and memory formation by regulating the association of CBP with CREB in the hippocampus. Our findings show that the aPKC-CBP pathway is required for hippocampal neuronal differentiation and maturation and hippocampal-dependent memory in mature adult (6 months old) mice, but not in young adult (3 months old) mice. Mechanistically, we found that the aPKC-CBP pathway is highly upregulated and is necessary to maintain the association of CBP with CREB in the hippocampus of mature mice when CREB activity (pS133-CREB) is reduced. More importantly, elevation of CREB activity (pS133-CREB) by a phosphodiesterase 4 (PDE4) inhibitor, rolipram, in the hippocampus can rescue the neuronal differentiation and maturation deficits in mature mice. This rescue is also accompanied by restoring impaired pre-exposure fear memory and the diminished binding of CBP to CREB in CbpS436A mice. Together, these data argue that the aPKC-CBP pathway has a compensatory homeostatic role in modulating hippocampal neurogenesis and hippocampal-dependent memory during early adulthood (3–6 months).