Article

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: 3.51). 03/2010; 518(5):647-67. DOI: 10.1002/cne.22235
Source: PubMed

ABSTRACT 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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    • "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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    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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    • "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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    ABSTRACT: The term epileptogenesis refers to a dynamic alteration in neuronal excitability that promotes the appearance of spontaneous seizures. Temporal lobe epilepsy, the most common type of acquired epilepsy, often develops after an insult to the brain such as trauma, febrile seizures, encephalitis, or status epilepticus. During the pre-epileptic state (also referred as latent or silent period) there is a plethora of molecular, biochemical, and structural changes that lead to the generation of recurrent spontaneous seizures (or epilepsy). The specific contribution of these alterations to epilepsy development is unclear, but a loss of inhibition has been associated with the increased excitability detected in the latent period. A rapid increase in neuronal hyperexcitability could be due, at least in part, to a decline in the number of physiologically active GABAA receptors (GABAAR). Altered expression of scaffolding proteins involved in the trafficking and anchoring of GABAAR could directly impact the stability of GABAergic synapses and promote a deficiency in inhibitory neurotransmission. Uncovering the molecular mechanisms operating during epileptogenesis and its possible impact on the regulation of GABAAR and scaffolding proteins may offer new targets to prevent the development of epilepsy.
    Frontiers in Cellular Neuroscience 07/2013; 7:113. DOI:10.3389/fncel.2013.00113 · 4.18 Impact Factor
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    • "Mossy Cell Loss Increases Dentate Excitability Neuron 76, 1189–1200, December 20, 2012 ª2012 Elsevier Inc. 1197 interneuronal loss and surviving interneurons affect dentate epileptogenesis (Cossart et al., 2005; Thind et al., 2010). Temporal lobe epileptogenesis may also involve entorhinal cortex and other related structures. "
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    ABSTRACT: Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity's net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5-6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation.
    Neuron 12/2012; 76(6):1189-200. DOI:10.1016/j.neuron.2012.10.036 · 15.98 Impact Factor
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