Abstract
Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson’s disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson’s disease.
Highlights
Neurogenesis in the Healthy and Parkinson’s Disease-Affected Brains1.1
We have demonstrated before that optogenetic stimulation of niche astrocytes expressing channelrhodopsin-2 under the Glial fibrillary acidic protein (GFAP) promoter was efficient in activating the neurogenic potential of neural stem cells (NSCs)/neural progenitor cells (NPCs) in the in vitro neurogenic niche model or in implanted intrahippocampal neurospheres ex vivo in experimental
The same phenomenon has not been reproduced in NSCs/NPCs yet, but it might be tempting to speculate that the positive effects of Wnt on dopaminergic neuron generation and survival are disrupted in Parkinson’s disease (PD) due to the abnormal activity of parkin and the overactivity of the Wnt/β-catenin signaling pathway could be modulated via connexin 43 (Cx43)-β-catenin interactions at the plasma membrane of
Summary
Neurogenesis is a mechanism of brain development and plasticity. Embryonic neurogenesis provides new neurons for brain growth, whereas adult neurogenesis is required for memory consolidation and tissue repair, mood regulation, and social recognition [1,2,3,4]. Even the addition of new neurons adultgyrus neurogenesis in rats resultsininvivo the elongation long-term potentiation toblocking the dentate of the hippocampus provides a of fresh substrate for new (LTP); newly-formed cells are required for the phenomenon of hippocampal memories, blocking adult neurogenesis in rats results in the elongation of long-term poclearance and consolidation of memory in extra-hippocampal brain regions [14]. Adult-born neurons inhibit the dentate gyrus activity by recruiting local interneurons, and it seems to be important for preventing memory interference and engrams overlapping in subsequent learning episodes (so-called cognitive flexibility) [13] This mechanism underlies the ability of young dentate gyrus cells to support pattern separation and the ability of old dentate gyrus cells to support rapid recall. That is why hyperexcitable dentate gyrus results in cognitive deficits and the impairment of pattern separation in mice [17]
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