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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior studies have not explicitly examined cell types and synaptic mechanisms for long-term seizure suppression. To address this gap, we transplanted medial ganglionic eminence (MGE) cells from embryonic day 13.5 VGAT-Venus or VGAT-ChR2-EYFP transgenic embryos into the dentate gyrus (DG) of adult mice 2 weeks after induction of TLE with pilocarpine. Beginning 3-4 weeks after status epilepticus, we conducted continuous video-electroencephalographic recording until 90-100 d. TLE mice with bilateral MGE cell grafts in the DG had significantly fewer and milder electrographic seizures, compared with TLE controls. Immunohistochemical studies showed that the transplants contained multiple neuropeptide or calcium-binding protein-expressing interneuron types and these cells established dense terminal arborizations onto the somas, apical dendrites, and axon initial segments of dentate granule cells (GCs). A majority of the synaptic terminals formed by the transplanted cells were apposed to large postsynaptic clusters of gephyrin, indicative of mature inhibitory synaptic complexes. Functionality of these new inhibitory synapses was demonstrated by optogenetically activating VGAT-ChR2-EYFP-expressing transplanted neurons, which generated robust hyperpolarizations in GCs. These findings suggest that fetal GABAergic interneuron grafts may suppress pharmacoresistant seizures by enhancing synaptic inhibition in DG neural circuits.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2014; 34(40):13492-504. DOI:10.1523/JNEUROSCI.0005-14.2014 · 6.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Convulsive status epilepticus is the most common neurological emergency in children and is associated with significant morbidity and mortality. The morbidities include later development of epilepsy, cognitive impairment, and psychiatric impairments. There has been a long-standing hypothesis that these outcomes are, at least in part, a function of brain injury induced by the status epilepticus. There is evidence from animal models and prospective human studies that the hippocampus may be injured during febrile status epilepticus although this pathophysiological sequence remains uncommon. Potential mechanisms include excitotoxicity, ischaemia, and inflammation. Neuroprotective drugs reduce brain injury but have little impact on epileptogenesis or cognitive impairments. Anti-inflammatory treatments have given mixed results to date. Broad-spectrum anti-inflammatory agents, such as steroids, are potentially harmful, whereas prevention of leucocyte diapedesis across the blood brain barrier appears to have a positive outcome. Therefore, more studies dissecting the inflammatory process are required to establish the most effective strategies for translation into clinical practice. In addition to neuronal loss, cognitive impairments are related to neuronal re-organisation and disruption of neural networks underpinning cognition. Further understanding of these mechanisms may lead to novel therapies that prevent brain injury, but also therapies that may improve outcomes even if injury has occurred.
    Epileptic disorders: international epilepsy journal with videotape 10/2014; 16(s1). DOI:10.1684/epd.2014.0689 · 0.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4 hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21 hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30 min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA. Copyright © 2014. Published by Elsevier Inc.
    Experimental Neurology 12/2014; 264. DOI:10.1016/j.expneurol.2014.11.009 · 4.62 Impact Factor