RGS6 Mediates Effects of Voluntary Running on Adult Hippocampal Neurogenesis.

Voluntary running enhances adult hippocampal neurogenesis, with consequences for hippocampal-dependent learning ability and mood regulation. However, the underlying mechanism remains unclear. Here, we show that voluntary running induces unique and dynamic gene expression changes specifically within the adult-born hippocampal neurons, with significant impact on genes involved in neuronal maturation and human diseases. We identify the regulator of G protein signaling 6 (RGS6) as a key factor that mediates running impact on adult-born neurons. RGS6 overexpression mimics the positive effects of voluntary running on morphological and physiological maturation of adult new neurons and reduced sensitivity of adult-born neurons to the inhibitory effect of GABAB (γ-Aminobutyric acid B) receptor activation. Knocking down RGS6 abolishes running-enhanced neuronal maturation and hippocampal neurogenesis-dependent learning and anxiolytic effect. Our study provides a data resource showing genome-wide intrinsic molecular changes in adult-born hippocampal neurons that contribute to voluntary running-induced neurogenesis.

Loss of MeCP2 in immature neurons leads to impaired network integration.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations or deletions in Methyl-CpG-binding Protein 2 (MeCP2), a brain-enriched transcriptional regulator. MeCP2 is highly expressed during neuronal maturation and its deficiency results in impaired dendritic morphogenesis and reduced dendritic spine numbers in developing neurons. However, whether MeCP2 deficiency impacts the integration of new neurons has not been directly assessed. In this study, we developed a modified rabies virus-mediated monosynaptic retrograde tracing method to interrogate presynaptic integration of MeCP2-deficient new neurons born in the adult hippocampus, a region with lifelong neurogenesis and plasticity. We found that selective deletion of MeCP2 in adult-born new neurons impaired their long-range connectivity to the cortex, whereas their connectivity within the local hippocampal circuits or with subcortical regions was not significantly affected. We further showed that knockdown of MeCP2 in primary hippocampal neurons also resulted in reduced network integration. Interestingly, (1-3) insulin-like growth factor-1 (IGF-1), a small peptide under clinical trial testing for RTT, rescued neuronal integration deficits of MeCP2-deficient neurons in vitro but not in vivo. In addition, (1-3) IGF-1 treatment corrected aberrant excitability and network synchrony of MeCP2-deficient hippocampal neurons. Our results indicate that MeCP2 is essential for immature neurons to establish appropriate network connectivity.