In the adult hippocampus, new neurons are generated in the dentate gyrus. The Wnt signaling pathway regulates this process, but little is known about the endogenous Wnt ligands involved. We investigated the role of Wnt5a on adult hippocampal neurogenesis. Wnt5a regulates neuronal morphogenesis during embryonic development, and maintains dendritic architecture of pyramidal neurons in the adult hippocampus. Here, we determined that Wnt5a knockdown in the mouse dentate gyrus by lentivirus‐mediated shRNA impaired neuronal differentiation of progenitor cells, and reduced dendritic development of adult‐born neurons. In cultured adult hippocampal progenitors (AHPs), Wnt5a knockdown reduced neuronal differentiation and morphological development of AHP‐derived neurons, whereas treatment with Wnt5a had the opposite effect. Interestingly, no changes in astrocytic differentiation were observed in vivo or in vitro, suggesting that Wnt5a does not affect fate‐commitment. By using specific inhibitors, we determined that Wnt5a signals through CaMKII to induce neurogenesis, and promotes dendritic development of newborn neurons through activating Wnt/JNK and Wnt/CaMKII signaling. Our results indicate Wnt5a as a niche factor in the adult hippocampus that promotes neuronal differentiation and development through activation of noncanonical Wnt signaling pathways.

Metabolic syndrome (MetS) is a global epidemic, which involves a spectrum of metabolic disorders comprising diabetes and obesity. The impact of MetS on the brain is becoming to be a concern, however, the poor understanding of mechanisms involved has limited the development of therapeutic strategies. We induced a MetS-like condition by exposing mice to fructose feeding for 7 weeks. There was a dramatic deterioration in the capacity of the hippocampus to sustain synaptic plasticity in the forms of long-term potentiation (LTP) and long-term depression (LTD). Mice exposed to fructose showed a reduction in the number of contact zones and the size of postsynaptic densities (PSDs) in the hippocampus, as well as a decrease in hippocampal neurogenesis. There was an increase in lipid peroxidation likely associated with a deficiency in plasma membrane excitability. Consistent with an overall hippocampal dysfunction, there was a subsequent decrease in hippocampal dependent learning and memory performance, i.e., spatial learning and episodic memory. Most of the pathological sequel of MetS in the brain was reversed three month after discontinue fructose feeding. These results are novel to show that MetS triggers a cascade of molecular events, which disrupt hippocampal functional plasticity, and specific aspects of learning and memory function. The overall information raises concerns about the risk imposed by excessive fructose consumption on the pathology of neurological disorders.

Neurogenesis persists during adulthood in the dentate gyrus of the hippocampus. Signals provided by the local hippocampal microenvironment support neural stem cell proliferation, differentiation, and maturation of newborn neurons into functional dentate granule cells, that integrate into the neural circuit and contribute to hippocampal function. Increasing evidence indicates that Wnt signaling regulates multiple aspects of adult hippocampal neurogenesis. Wnt ligands bind to Frizzled receptors and co-receptors to activate the canonical Wnt/β-catenin signaling pathway, or the noncanonical β-catenin-independent signaling cascades Wnt/Ca 2+ and Wnt/planar cell polarity. Here, we summarize current knowledge on the roles of Wnt signaling components including ligands, receptors/co-receptors and soluble modulators in adult hippocampal neurogenesis. Also, we review the data suggesting distinctive roles for canonical and non-canonical Wnt signaling cascades in regulating different stages of neurogenesis. Finally, we discuss the evidence linking the dysfunction of Wnt signaling to the decline of neurogenesis observed in aging and Alzheimer's disease.

Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected.

SummaryThe CD73 ectonucleotidase catalyses the hydrolysis of AMP to adenosine, an immunosuppressive molecule. Recent evidence has demonstrated that this ectonucleotidase is up-regulated in T helper type 17 cells when generated in the presence of transforming growth factor-b (TGF-b), and hence CD73 expression is related to the acquisition of immunosuppressive potential by these cells. TGF-b is also able to induce CD73 expression in CD8 + T cells but the function of this ectonucleotidase in CD8 + T cells is still unknown. Here, we show that Tc17 cells present high levels of the CD73 ectonucleotidase and produce adenosine; however, they do not suppress the proliferation of CD4 + T cells. Interestingly, we report that adenosine signalling through A2A receptor favours interleukin-17 production and the expression of stem cell-associated transcription factors such as tcf-7 and lef-1 but restrains the acquisition of Tc1-related effector molecules such as interferon-c and Granzyme B by Tc17 cells. Within the tumour microenvironment, CD73 is highly expressed in CD62L + CD127 + CD8 + T cells (memory T cells) and is down-regulated instrating that CD73 is expressed in memory/naive cells and is down-regulated during differentiation. These data reveal a novel function of CD73 ectonucleotidase in arresting CD8 + T-cell differentiation and support the idea that CD73-driven adenosine production by Tc17 cells may promote stem cell-like properties in Tc17 cells.

Background Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. Results Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. Conclusions NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.

Klotho is an aging-related protein associated with hippocampal cognitive performance in mammals. Klotho regulates progenitor cell proliferation in non-neuronal tissues, but its role in adult hippocampal neurogenesis (AHN) has not been explored. Klotho expression in the adult mouse hippocampus was examined by immunofluorescence and PCR. AHN was evaluated in the hippocampus of klotho knock-out mice (KO), klotho KO/vitamin D-receptor mutant mice, and in a model of local klotho hippocampal knockdown. The recombinant Klotho effect on proliferation was measured in mouse-derived hippocampal neural progenitor cells. Hippocampal-dependent memory was assessed by a dry-land version of the Morris water maze. Klotho was expressed in the granular cell layer of the adult Dentate Gyrus. AHN was increased in klotho KO mice, but not in klotho KO/vitamin D-receptor mutant mice. Inversely, local downregulation of hippocampal Klotho diminished AHN. Recombinant Klotho increased the proliferation rate of neural progenitors. Downregulation of hippocampal Klotho correlated with a decreased performance in hippocampal dependent memory. These results suggest that Klotho directly participates in regulating AHN. Our observations indicate that Klotho promotes proliferation, AHN and hippocampal dependent cognition. Increased neurogenesis in klotho KO mice may be secondary to the activation of other pathways altered in the model, such as vitamin D.

In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.