Article

Postnatal and adult neurogenesis in the development of human disease

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
The Neuroscientist (Impact Factor: 7.62). 11/2008; 14(5):446-58. DOI: 10.1177/1073858408317008
Source: PubMed

ABSTRACT The mammalian brain contains a population of neurons that are continuously generated from late embryogenesis through adulthood-after the generation of almost all other neuronal types. This brain region-the hippocampal dentate gyrus-is in a sense, therefore, persistently immature. Postnatal and adult neurogenesis is likely an essential feature of the dentate, which is critical for learning and memory. Protracted neurogenesis after birth would allow the new cells to develop in conjunction with external events-but it may come with a price: while neurogenesis in utero occurs in a protected environment, children and adults are exposed to any number of hazards, such as toxins and infectious agents. Mature neurons might be resistant to such exposures, but new neurons may be vulnerable. Consistent with this prediction, in adult rodents seizures disrupt the integration of newly generated granule cells, whereas mature granule cells are comparatively unaffected. Significantly, abnormally interconnected cells may contribute to epileptogenesis and/or associated cognitive and memory deficits. Finally, studies increasingly indicate that new granule cells are extremely sensitive to a host of endogenous and exogenous factors, raising the possibility that disrupted granule cell integration may be a common feature of many neurological diseases.

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    • "Along the same lines, mRNA from surgical specimens of patients with chronic refractory TLE demonstrates significantly increased levels of NKCC1, the chloride channel associated with depolarizing GABAergic interneurons (Palma et al., 2006). While aberrant cell proliferation and differentiation may be a driver of epileptogenesis, the mechanisms linking the initial epileptic insult to changes in cell fate and differentiation remain elusive (Danzer, 2008). Given the rapid proliferation and differentiation of neural progenitor stem cells (NPSCs) throughout the immature brain, pathological effects of an inciting epileptic event on NPSCs have the potential to have a particularly profound effect on the subsequent development of TLE and other refractory epilepsies. "
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    ABSTRACT: While aberrant cell proliferation and differentiation may contribute to epileptogenesis, the mechanisms linking an initial epileptic insult to subsequent changes in cell fate remain elusive. Using both mouse and human iPSC-derived neural progenitor/stem cells (NPSCs), we found that a combined transient muscarinic and mGluR1 stimulation inhibited overall neurogenesis but enhanced NPSC differentiation into immature GABAergic cells. If treated NPSCs were further passaged, they retained a nearly identical phenotype upon differentiation. A similar profusion of immature GABAergic cells was seen in rats with pilocarpine-induced chronic epilepsy. Furthermore, live cell imaging revealed abnormal de-synchrony of Ca(++) transients and altered gap junction intercellular communication following combined muscarinic/glutamatergic stimulation, which was associated with either acute site-specific dephosphorylation of connexin 43 or a long-term enhancement of its degradation. Therefore, epileptogenic stimuli can trigger acute and persistent changes in cell fate by altering distinct mechanisms that function to maintain appropriate intercellular communication between coupled NPSCs.
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    • "Asterisk denotes basal dendrites on immature granule cells. Scale bar = 30 μm. Figure reprinted with permission from Danzer [179] (Copyright © 2008 Sage Publications). Fig. 2. Normal and abnormal hippocampal dentate granule cells of pilocarpine-treated Gli1-CreER T2 × GFP reporter mice. "
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    • "The hippocampus is believed to be one brain area important for epileptogenesis, and TLE is associated with reduced hippocampal tissue volume and malformation (Bernasconi et al., 2005; Renard et al., 2011; Seidenberg et al., 2005) and abnormal architecture of hippocampal regions such as the dentate gyrus (Bluemcke et al., 2002; Danzer, 2008). Although research has produced mixed results, TLE has been linked with abnormal neurogenesis and/or migration of dentate gyrus granule neurons (Crespel et al., 2005; Danzer, 2008; Fahrner et al., 2007; Kuruba et al., 2009). "
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