Initial loss but later excess of GABAergic synapses with dentate granule cells in a rat model of temporal lobe epilepsy. J Comp Neurol

Department of Comparative Medicine, Stanford University, California 94305, USA.
The Journal of Comparative Neurology (Impact Factor: 3.23). 03/2010; 518(5):647-67. DOI: 10.1002/cne.22235
Source: PubMed


Many patients with temporal lobe epilepsy display neuron loss in the dentate gyrus. One potential epileptogenic mechanism is loss of GABAergic interneurons and inhibitory synapses with granule cells. Stereological techniques were used to estimate numbers of gephyrin-positive punctae in the dentate gyrus, which were reduced short-term (5 days after pilocarpine-induced status epilepticus) but later rebounded beyond controls in epileptic rats. Stereological techniques were used to estimate numbers of synapses in electron micrographs of serial sections processed for postembedding GABA-immunoreactivity. Adjacent sections were used to estimate numbers of granule cells and glutamic acid decarboxylase-positive neurons per dentate gyrus. GABAergic neurons were reduced to 70% of control levels short-term, where they remained in epileptic rats. Integrating synapse and cell counts yielded average numbers of GABAergic synapses per granule cell, which decreased short-term and rebounded in epileptic animals beyond control levels. Axo-shaft and axo-spinous GABAergic synapse numbers in the outer molecular layer changed most. These findings suggest interneuron loss initially reduces numbers of GABAergic synapses with granule cells, but later, synaptogenesis by surviving interneurons overshoots control levels. In contrast, the average number of excitatory synapses per granule cell decreased short-term but recovered only toward control levels, although in epileptic rats excitatory synapses in the inner molecular layer were larger than in controls. These findings reveal a relative excess of GABAergic synapses and suggest that reports of reduced functional inhibitory synaptic input to granule cells in epilepsy might be attributable not to fewer but instead to abundant but dysfunctional GABAergic synapses.

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Available from: Ruth Yamawaki, Apr 01, 2015
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    • "Elavl4 has been shown to be expressed in interneurons in the hippocampus (Bolognani et al., 2004), and it has been shown to be involved in transporting mRNA in neuronal processes, leading to neurite outgrowth and changes in neuroplasticity (Aronov et al., 2002; Bolognani et al., 2007; Tanner et al., 2008). These processes could underlie several alterations in inhibitory interneurons or dentate granule neurons that have been observed in the epileptic brain, including increased axonal growth and synaptogenesis (Dudek and Sutula, 2007; Thind et al., 2010). In addition, properties of synaptic vesicle release probabilities have been shown to be altered in interneurons and mossy fibers in epileptic animals (Goussakov et al., 2000; Kobayashi and Buckmaster, 2003). "
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    ABSTRACT: The molecular basis of epileptogenesis is poorly characterized. Studies in humans and animal models have identified an electrophysiological signature that precedes the onset of epilepsy, which has been termed fast ripples (FRs) based on its frequency. Multiple lines of evidence implicate regions generating FRs in epileptogenesis, and FRs appear to demarcate the seizure onset zone, suggesting a role in ictogenesis as well. We performed gene expression analysis comparing areas of the dentate gyrus that generate FRs to those that do not generate FRs in a well-characterized rat model of epilepsy. We identified a small cohort of genes that are differentially expressed in FR versus non-FR brain tissue and used quantitative PCR to validate some of those that modulate neuronal excitability. Gene expression network analysis demonstrated conservation of gene co-expression between non-FR and FR samples, but examination of gene connectivity revealed changes that were most pronounced in the cm-40 module, which contains several genes associated with synaptic function and the differentially expressed genes Kcna4, Kcnv1, and Npy1r that are down-regulated in FRs. We then demonstrate that the genes within the cm-40 module are regulated by seizure activity and enriched for the targets of the RNA binding protein Elavl4. Our data suggest that seizure activity induces co-expression of genes associated with synaptic transmission and that this pattern is attenuated in areas displaying FRs, implicating the failure of this mechanism in the generation of FRs. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 03/2015; 78. DOI:10.1016/j.nbd.2015.02.011 · 5.08 Impact Factor
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    • "Studies in animal models of temporal lobe epilepsy (TLE) have demonstrated increased neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) (Parent et al., 1997; Sankar et al., 2000). In addition, while many studies have noted a loss of GABAergic interneurons from the hilus of chronic TLE brains, others have shown an increase in GABAergic synapses within DG cells as well as increased expression of the GABAergic markers GAD67 and GAD65 (Esclapez and Houser, 1999; Sun et al., 2014; Thind et al., 2010). This seeming paradox may be partly attributable to either a compensatory response to over excitation or to the persistence of GABA (A) receptor-induced depolarization, normally a feature of GABA action early in neurodevelopment (Young et al., 2012). "
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    Neurobiology of Disease 07/2014; 70. DOI:10.1016/j.nbd.2014.06.020 · 5.08 Impact Factor
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    • "If a loss of gephyrin directly impacts the number and function of GABA A R at inhibitory synapses, interventions to promote the stability of gephyrin and GABA A R might ameliorate the deleterious changes in excitability observed during epileptogenesis and epilepsy. Altered expression of gephyrin has been observed in several pathologies presenting symptomatic seizures, but it is unclear if changes in gephyrin are beneficial or pathologic (Jakubs et al., 2008; Thind et al., 2010; Jackson et al., 2012). Understanding the molecular mechanism(s) behind the dysregulation of scaffolding proteins involved in the regulation of GABA A R might provide new insights into the pathologic events that contribute to the generation of spontaneous seizures and might offer new targets to disrupt epileptogenesis and prevent epilepsy. "
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