Regulation of neurogenesis and cerebral angiogenesis by cell protein proteolysis products

Brain development is a unique process characterized by mechanisms defined as neuroplasticity (synaptogenesis, synapse elimination, neurogenesis, and cerebral angiogenesis). Numerous neurodevelopmental disorders brain damage, and aging are manifested by neurological deficits that are caused by aberrant neuroplasticity. The presence of stem and progenitor cells in neurogenic niches of the brain is responsible for the formation of new neurons capable of integrating into preexisting synaptic assemblies. The determining factors for the cells within the neurogenic niche are the activity of the vascular scaffold and the availability of active regulatory molecules that establish the optimal microenvironment. It has been found that regulated intramembrane proteolysis plays an important role in the control of neurogenesis in brain neurogenic niches. Molecules generated by the activity of specific proteases can stimulate or suppress the activity of neural stem and progenitor cells, their proliferation and differentiation, migration and integration of newly formed neurons into synaptic networks. Local neoangiogenesis supports the processes of neurogenesis in neurogenic niches, which is guaranteed by the multivalent action of peptides formed from transmembrane proteins. Identification of new molecules regulating the neuroplasticity (neurogenesis and angiogenesis). i. e. enzymes, substrates, and products of intramembrane proteolysis, will ensure the development of protocols for detecting the neuroplasticity markers and targets for efficient pharmacological modulation.

Cylindromatosis Drives Synapse Pruning and Weakening by Promoting Macroautophagy through Akt-mTOR Signaling

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux and, conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

Stroke subtype-dependent synapse elimination by reactive gliosis in mice

The pathological role of reactive gliosis in CNS repair remains controversial. In this study, using murine ischemic and hemorrhagic stroke models, we demonstrated that microglia/macrophages and astrocytes are differentially involved in engulfing synapses in the reactive gliosis region. By specifically deleting MEGF10 and MERTK phagocytic receptors, we determined that inhibiting phagocytosis of microglia/macrophages or astrocytes in ischemic stroke improved neurobehavioral outcomes and attenuated brain damage. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed that phagocytosis related biological processes and pathways were downregulated in astrocytes of the hemorrhagic brain compared to the ischemic brain. Together, these findings suggest that reactive microgliosis and astrogliosis play individual roles in mediating synapse engulfment in pathologically distinct murine stroke models and preventing this process could rescue synapse loss.

Single-cell RNA transcriptome analysis reveals CXCL16/CXCR6 as maintenance factors for CNS tissue resident T cells that drive synapse elimination during viral recovery

Background: Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS resident memory T (TRM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown. Methods: Here, we examined the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation, genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. Results: Profiling of host transcriptome at 25 days post-infection revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TRM cell biology, was identified as critically regulating CXCR6 expressing CD8+ TRM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8+ T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 is required not only for the maintenance of WNV-specific, CD8 TRM cells in the post-infectious CNS, but also contributes to their expression of TRM cell markers. Moreover, CXCR6+CD8+ T cells are required for glial activation and ongoing synapse elimination. Conclusions: We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8+ T cells that maintains forebrain TRM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 during recovery may reduce CNS CD8+ TRM cells.

Autophagy in DG engrams mediates Rac1-dependent forgetting during aging via microglia-mediated synapse elimination

Engrams are considered to be substrates for memory storage, and the functional dysregulation of the engrams leads to cognition impairment. However, the pathological changes of the engrams leading to forgetting, which typically involves a failure in memory retrieval, remains unclear. Here we found that the expression of autophagy protein 7 (Atg7) in dentate gyrus (DG) engrams was dramatically increased in aged mice, leading to the activation of surrounding microglia and impair retrieval of conditioned fear memory. Using transcriptomic and fluorescence in situ hybridization analyses, we demonstrated Toll-like receptor (TLR) pathway were upregulated in DG microglia by overexpressing ATG7 in DG engrams. TLR2/4 in the microglia mediates the excessive synapse elimination and impaired retrieval of fear memory induced by ATG7-depedent autophagy in DG engrams. The expression of Rac1, a Rho-GTPases which mediates active forgetting, was upregulated in aged engrams. Optogenetic activation of Rac1 in DG engrams promoted the expression of ATG7 and autophagy in the engrams, the activation of microglia, and thus impaired the retrieval of fear memory. Interference of the Atg7 expression in the engram and microglia activation prevented the impairment of fear memory retrieval induced by activation of Rac1 in DG engrams. Together, our findings revealed autophagy-dependent remodeling of DG engrams by microglia as a novel interference mechanism of memory retrieval.

Pruning of Deep Spiking Neural Networks through Gradient Rewiring

Spiking Neural Networks (SNNs) have been attached great importance due to their biological plausibility and high energy-efficiency on neuromorphic chips. As these chips are usually resource-constrained, the compression of SNNs is thus crucial along the road of practical use of SNNs. Most existing methods directly apply pruning approaches in artificial neural networks (ANNs) to SNNs, which ignore the difference between ANNs and SNNs, thus limiting the performance of the pruned SNNs. Besides, these methods are only suitable for shallow SNNs. In this paper, inspired by synaptogenesis and synapse elimination in the neural system, we propose gradient rewiring (Grad R), a joint learning algorithm of connectivity and weight for SNNs, that enables us to seamlessly optimize network structure without retraining. Our key innovation is to redefine the gradient to a new synaptic parameter, allowing better exploration of network structures by taking full advantage of the competition between pruning and regrowth of connections. The experimental results show that the proposed method achieves minimal loss of SNNs' performance on MNIST and CIFAR-10 datasets so far. Moreover, it reaches a ~3.5% accuracy loss under unprecedented 0.73% connectivity, which reveals remarkable structure refining capability in SNNs. Our work suggests that there exists extremely high redundancy in deep SNNs. Our codes are available at https://github.com/Yanqi-Chen/Gradient-Rewiring.