Article

Functional integration of new hippocampal neurons following insults to the adult brain is determined by characteristics of pathological environment.

Laboratory of Neurogenesis and Cell Therapy, Lund University Hospital, SE-221 84 Lund, Sweden.
Experimental Neurology (Impact Factor: 4.62). 03/2011; 229(2):484-93. DOI: 10.1016/j.expneurol.2011.03.019
Source: PubMed

ABSTRACT We have previously shown that following severe brain insults, chronic inflammation induced by lipopolysaccharide (LPS) injection, and status epilepticus, new dentate granule cells exhibit changes of excitatory and inhibitory synaptic drive indicating that they may mitigate the abnormal brain function. Major inflammatory changes in the environment encountering the new neurons were a common feature of these insults. Here, we have asked how the morphology and electrophysiology of new neurons are affected by a comparably mild pathology: repetitive seizures causing hyperexcitability but not inflammation. Rats were subjected to rapid kindling, i.e., 40 rapidly recurring, electrically-induced seizures, and subsequently exposed to stimulus-evoked seizures twice weekly. New granule cells were labeled 1 week after the initial insult with a retroviral vector encoding green fluorescent protein. After 6-8 weeks, new neurons were analyzed using confocal microscopy and whole-cell patch-clamp recordings. The new neurons exposed to the pathological environment exhibited only subtle changes in their location, orientation, dendritic arborizations, and spine morphology. In contrast to the more severe insults, the new neurons exposed to rapid kindling and stimulus-evoked seizures exhibited enhanced afferent excitatory synaptic drive which could suggest that the cells that had developed in this environment contributed to hyperexcitability. However, the new neurons showed concomitant reduction of intrinsic excitability which may counteract the propagation of this excitability to the target cells. This study provides further evidence that following insults to the adult brain, the pattern of synaptic alterations at afferent inputs to newly generated neurons is dependent on the characteristics of the pathological environment.

0 Followers
 · 
152 Views
  • [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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whether severe epilepsy could be a progressive disorder remains as yet unresolved. We previously demonstrated in a rat model of acquired focal cortical dysplasia, the methylazoxymethanol/pilocarpine - MAM/pilocarpine - rats, that the occurrence of status epilepticus (SE) and subsequent seizures fostered a pathologic process capable of modifying the morphology of cortical pyramidal neurons and NMDA receptor expression/localization. We have here extended our analysis by evaluating neocortical and hippocampal changes in MAM/pilocarpine rats at different epilepsy stages, from few days after onset up to six months of chronic epilepsy. Our findings indicate that the process triggered by SE and subsequent seizures in the malformed brain i) is steadily progressive, deeply altering neocortical and hippocampal morphology, with atrophy of neocortex and CA regions and progressive increase of granule cell layer dispersion; ii) changes dramatically the fine morphology of neurons in neocortex and hippocampus, by increasing cell size and decreasing both dendrite arborization and spine density; iii) induces reorganization of glutamatergic and GABAergic networks in both neocortex and hippocampus, favoring excitatory vs inhibitory input; iv) activates NMDA regulatory subunits. Taken together, our data indicate that, at least in experimental models of brain malformations, severe seizure activity, i.e., SE plus recurrent seizures, may lead to a widespread, steadily progressive architectural, neuronal and synaptic reorganization in the brain. They also suggest the mechanistic relevance of glutamate/NMDA hyper-activation in the seizure-related brain pathologic plasticity.
    PLoS ONE 02/2014; 9(2):e89898. DOI:10.1371/journal.pone.0089898 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is unclear to what extent neuropathological changes contribute to brain inflammation observed in temporal lobe epilepsy (TLE). Here, we compared cytokine levels between histopathologically-confirmed sclerotic hippocampi and histopathologically-confirmed normal hippocampi from TLE patients. We analyzed a similar cytokine panel in hippocampi from amygdala-kindled rats and we evaluated neuropathological changes by immunohistochemistry. In TLE patients, cytokine levels were not significantly different between sclerotic and non-sclerotic hippocampi. Though kindling resulted in increased astrocyte activation, cytokine levels and microglia activation were unchanged. These results suggest that the chronic epileptic state in TLE can also occur in the absence of intracerebral inflammation. Highligths •HS in TLE patients is not associated with a sustained brain inflammatory response.•Amygdala kindled seizures are not associated with a sustained inflammatory response.•Brain inflammation is not necessarily present in temporal lobe epilepsy.
    Journal of neuroimmunology 06/2014; DOI:10.1016/j.jneuroim.2014.03.016 · 2.79 Impact Factor

Full-text (2 Sources)

Download
40 Downloads
Available from
Jun 2, 2014