IL-10 regulates adult neurogenesis by modulating ERK and STAT3 activity

The adult subventricular zone (SVZ) contains Nestin+ progenitors that differentiate mainly into neuroblasts. Our previous data showed that interleukin-10 (IL-10) regulates SVZ adult neurogenesis by up-regulating the expression of pro-neural genes and modulating cell cycle exit. Here we addressed the specific mechanism through which IL-10 carries out its signaling on SVZ progenitors. We found that,in vitro andin vivo, IL-10 targets Nestin+ progenitors and activates the phosphorylation of ERK and STAT3. The action of IL-10 on Nestin+ progenitors is reversed by treatment with a MEK/ERK inhibitor, thus restoring neurogenesis to normal levels. Silencing STAT3 expression by lentiviral vectors also impaired neurogenesis by blocking the effects of IL-10. Our findings unveil ERK and STAT3 as effectors of IL-10 in adult SVZ neurogenesis. © 2015, Frontiers Research Foundation. All rights reservedThis work was supported by Marató TV3, and Mapfre foundation to EP. EP was a researcher of the Ramón y Cajal program (MICINN Spain).Peer Reviewe

rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration

Background Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra. Results We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants. Conclusions In conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7

Chemogenetic therapy strongly suppresses hippocampal excitability and spontaneous seizures in a rat model for temporal lobe epilepsy

The hippocampus plays a crucial role in seizure generation in temporal lobe epilepsy (TLE), a common form of medication-resistant epilepsy. This preclinical study evaluated chemogenetics as a therapy for TLE. In this approach, excitatory neurons of the epileptic hippocampus were selectively inhibited through ligand-based activation of an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD). The intraperitoneal kainic acid rat model for TLE was used. Animals were injected in right hippocampus with adeno-associated viral vector carrying CamKIIα-hM4Di-mCherry. Two weeks after injection, rats were implanted with electrodes. Dentate gyrus excitability was assessed by recording perforant path evoked potentials (EPs; n=8) before and after activating DREADDs with subclinical doses of clozapine (0.1 mg/kg, s.c.). Seizure suppression was determined using continuous video-EEG recordings (n=7) during a baseline period of seven days and three days of treatment with clozapine (0.1 mg/kg/24h, s.c.). Clozapine-induced activation of DREADDs suppressed synaptic transmission (field excitatory postsynaptic potential amplitude and slope reduced with 73%±12% and 65%±12% respectively) and postsynaptic neuronal activation (population spike surface area reduced with 53%±18) in dentate gyrus. In addition, in four of seven animals, DREADD activation led to complete suppression of spontaneous seizures for two to five hours. Activating hM4Di DREADDs in excitatory hippocampal neurons decreases excitability of dentate gyrus and temporary suppresses spontaneous seizures in a rat model for TLE. We believe that after optimization, this technique will lead to prolonged seizure freedom, making it a promising tool for clinical applications