Postnatal and adult neurogenesis in the development of human disease
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.
- SourceAvailable from: Roberto Di Maio
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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. "
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.Neurobiology of Disease 07/2014; 70. DOI:10.1016/j.nbd.2014.06.020 · 5.20 Impact Factor
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- "Asterisk denotes basal dendrites on immature granule cells. Scale bar = 30 μm. Figure reprinted with permission from Danzer  (Copyright © 2008 Sage Publications). Fig. 2. Normal and abnormal hippocampal dentate granule cells of pilocarpine-treated Gli1-CreER T2 × GFP reporter mice. "
ABSTRACT: Temporal lobe epilepsy in both animals and humans is characterized by abnormally integrated hippocampal dentate granule cells. Among other abnormalities, these cells make axonal connections with inappropriate targets, grow dendrites in the wrong direction, and migrate to ectopic locations. These changes promote the formation of recurrent excitatory circuits, leading to the appealing hypothesis that these abnormal cells may by epileptogenic. While this hypothesis has been the subject of intense study, less attention has been paid to the possibility that abnormal granule cells in the epileptic brain may also contribute to comorbidities associated with the disease. Epilepsy is associated with a variety of general findings, such as memory disturbances and cognitive dysfunction, and is often comorbid with a number of other conditions, including schizophrenia and autism. Interestingly, recent studies implicate disruption of common genes and gene pathways in all three diseases. Moreover, while neuropsychiatric conditions are associated with changes in a variety of brain regions, granule cell abnormalities in temporal lobe epilepsy appear to be phenocopies of granule cell deficits produced by genetic mouse models of autism and schizophrenia, suggesting that granule cell dysmorphogenesis may be a common factor uniting these seemingly diverse diseases. Disruption of common signaling pathways regulating granule cell neurogenesis may begin to provide mechanistic insight into the cooccurrence of temporal lobe epilepsy and cognitive and behavioral disorders. This article is part of a Special Issue entitled "NEWroscience 2013".Epilepsy & Behavior 01/2014; 38. DOI:10.1016/j.yebeh.2013.12.022 · 2.06 Impact Factor
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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). "
ABSTRACT: Temporal lobe epilepsy is believed to develop after an initial precipitating injury, usually suffered in childhood or adolescence, and aspects include impaired maturation of the hippocampus, and specifically the dentate gyrus. The dentate gyrus receives a major serotonergic input from the brainstem raphe nuclei, and the serotonergic system may regulate neurogenesis in the developing and mature hippocampus. The aim of this work was to investigate changes which may be associated with abnormal functioning of the serotonergic system in the pilocarpine model of epilepsy, where spontaneous seizures are induced by administration of pilocarpine at 6weeks of age. Application of serotonin (100μM) led to a transient hyperpolarization of the resting membrane potential and decrease of the input resistance mediated by the 5-HT(1A) receptor that was similar between control and pilocarpine-treated animals and unaffected by the age of the animal. In the younger, but not in older control animals, serotonin led to a 5-HT(2) receptor-mediated long-term depression of evoked postsynaptic currents, a normal functional shift in the early adulthood of the Wistar rat. In pilocarpine-treated animals, this long-term depression persisted in older animals, indicating impaired maturation of the dentate gyrus. These data may indicate 5-HT(2) receptor function to be affected by the pathology of temporal lobe epilepsy.Neurobiology of Disease 10/2012; 50(1). DOI:10.1016/j.nbd.2012.10.012 · 5.20 Impact Factor