Williams‐Beuren syndrome (WBS) is a microdeletion disorder with cognitive phenotype. NSUN5 gene, which encodes a cytosine‐5 RNA methyltransferase, is located in WBS deletion locus. To investigate the influence of NSUN5 deletion on cognitive behaviors, we produced single‐gene Nsun5 knockout (Nsun5‐KO) mice. Here, we report that adult Nsun5‐KO mice showed spatial cognitive deficits. Size of the brain and hippocampal structures and the number of CA1 or CA3 pyramidal cells in Nsun5‐KO mice did not differ from WT mice. Basal properties of Schaffer collateral‐CA1 synaptic transmission in Nsun5‐KO mice were unchanged, but NMDA receptor (NMDAr)‐dependent long‐term potentiation (LTP) was not induced. The NMDA‐evoked current in CA1 pyramidal cells was reduced in Nsun5‐KO mice without the changes in expression and phosphorylation of NMDAr subunits NR2A and NR2B. Although the protein level of AMPA receptor subunit GluR2 was attenuated in Nsun5‐KO mice, the AMPA‐evoked current was not altered. Hippocampal immuno‐staining showed the selective expression of Nsun5 in NG2 or PDGFRα labeled oligodendrocyte precursor cells (OPCs), but not in pyramidal cells or astrocytes. Analysis of RT‐PCR determined the Nsun5 expression in purified populations of OPCs rather than neurons or astrocytes. The Nsun5 deficiency led to decreases in the number and neurite outgrowth of OPCs in the hippocampal CA1 and DG, with the decline in NG2 expression and OPCs proliferation. These findings indicate that the Nsun5 deletion suppresses NMDAr activity in neuronal cells probably through the disrupted development and function of OPCs, leading to deficits in NMDAr‐dependent LTP and spatial cognitive abilities.

Nsun5 gene, encoding a cytosine-5 RNA methyltransferase, is deleted in about 95% patients with Williams-Beuren syndrome (WBS). WBS is a neurodevelopmental disorder and characterized by cognitive disorder. We generated single-gene Nsun5 knockout ( Nsun5 -KO) mice and reported that the Nsun5 deletion leads to deficit in spatial cognition. This study focused on investigating the influence of Nsun5 deficiency in the development of cerebral cortex. In comparison with wild-type littermates, the cortical thickness in postnatal day 10 Nsun5 -KO mice was obviously reduced with an abnormal laminar organization, and the processes of pyramidal cells were shorter and finer. Nsun5 was selectively expressed in radial glial cells (RGCs) of cerebral cortex from embryonic day (E) 12.5 to E16.5, but not in intermediate progenitor cells (IPCs) or neocortical neurons. The Nsun5 deletion did not alter proliferation of RGCs or differentiation of RGCs into IPCs. Notably, the ablation of Nsun5 disrupted the growth of radial glial scaffolds, thus numerous basal processes of RGCs failed to reach pial basement membrane. Level of cell polarity regulator Cdc42 protein in radial glial scaffolds of E14.5 Nsun5 -KO mice was reduced, but the level of Cdc42 mRNA was unchanged. The dysfunction of glial scaffolds impeded the radial migration of upper-layer and deeper-layer neurons to cause their subcortical accumulation and apoptosis, resulting in an obvious thinness of the cortical plate in E18.5 Nsun5 -KO mice. These findings establish a critical role of Nsun5 in development of cerebral cortex through regulating radial glial scaffolds of RGCs to control migration of neocortical neurons. Electronic supplementary material The online version of this article (10.1186/s13041-019-0496-6) contains supplementary material, which is available to authorized users.

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Akt signaling has been associated with adult neurogenesis in the hippocampal dentate gyrus (DG). We reported cognitive dysfunction in Akt3 knockout (Akt3-KO) mice with the down-regulation of mTOR activation. However, little is known about the effects of Akt3 signaling on hippocampal neurogenesis. Herein, we show that progenitor cells, neuroblasts, and mature newborn neurons in hippocampal DG expressed Akt3 protein. The Akt3 phosphorylation in hippocampal DG was increased after voluntary wheel running for 7 days in wild-type mice (running WT mice), but not in Akt3-KO mice (running Akt3-KO mice). Subsequently, we observed that the proliferation of progenitor cells was suppressed in Akt3-KO mice and the mTOR inhibitor rapamycin-treated mice, whereas enhanced in running WT mice rather than running Akt3-KO mice. Neurite growth of neuroblasts was impaired in Akt3-KO mice and rapamycin-treated mice. In contrast, neither differentiation of progenitor cells nor migrating of newly generated neurons was altered in Akt3-KO mice or running WT mice. The levels of p70S6K and 4EBP1 phosphorylation were declined in Akt3-KO mice and elevated in running WT mice depending on mTOR activation. Furthermore, telomerase activity, telomere length, and expression of telomerase reverse transcriptase (TERT) were decreased in Akt3-KO mice but increased in running WT mice rather than running Akt3-KO mice, which required the mTOR activation. The study provides in vivo evidence that Akt3-mTOR signaling plays an important role in the proliferation of progenitor cells and neurite growth through positive regulated TERT expression and activation of p70S6K and 4EBP1.