Morpho-Physiologic Characteristics of Dorsal Subicular Network in Mice after Pilocarpine-Induced Status Epilepticus

Epilepsy Research Lab, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, Singapore.
Brain Pathology (Impact Factor: 3.84). 03/2009; 20(1):80-95. DOI: 10.1111/j.1750-3639.2009.00243.x
Source: PubMed


The goal of this study was to examine the morpho-physiologic changes in the dorsal subiculum network in the mouse model of temporal lobe epilepsy using extracellular recording, juxtacellular and immunofluorescence double labeling, and anterograde tracing methods. A significant loss of total dorsal subicular neurons, particularly calbindin, parvalbumin (PV) and immunopositive interneurons, was found at 2 months after pilocarpine-induced status epilepticus (SE). However, the sprouting of axons from lateral entorhinal cortex (LEnt) was observed to contact with surviving subicular neurons. These neurons had two predominant discharge patterns: bursting and fast irregular discharges. The bursting neurons were mainly pyramidal cells, and their dendritic spine density and bursting discharge rates were increased significantly in SE mice compared with the control group. Fast irregular discharge neurons were PV-immunopositive interneurons and had less dendritic spines in SE mice when compared with the control mice. When LEnt was stimulated, bursting and fast irregular discharge neurons had much shorter latency and stronger excitatory response in SE mice compared with the control group. Our results illustrate that morpho-physiologic changes in the dorsal subiculum could be part of a multilevel pathologic network that occurs simultaneously in many brain areas to contribute to the generation of epileptiform activity.

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    • "Epilepsy is a neuronal disorder that is characterized by the abnormal, continued discharge and hypersynchronous activity of neurons [1]. The existing models of epilepsy provide good tools to study the basic mechanisms by which seizures are generated, and the model of temporal lobe epilepsy (TLE) induced by pilocarpine or kainic acid (KA) simulates most of the characteristics of this pathology [2–4]. In this TLE model, high frequency oscillations known as fast ripples (FRs, 250–600 Hz) have been observed, as in tetrodotoxin and tetanus toxin models of epilepsy [5–7], in computational models in silico [8, 9] and in patients with TLE [2, 10, 11]. "
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    ABSTRACT: Background: In models of temporal lobe epilepsy and in patients with this pathology, high frequency oscillations called fast ripples (FRs, 250-600 Hz) can be observed. FRs are considered potential biomarkers for epilepsy and, in the light of many in vitro and in silico studies, we thought that electrical synapses mediated by gap junctions might possibly modulate FRs in vivo. Methods: Animals with spontaneous recurrent seizures induced by pilocarpine administration were implanted with movable microelectrodes in the right anterior and posterior hippocampus to evaluate the effects of gap junction blockers administered in the entorhinal cortex. The effects of carbenoxolone (50 nmoles) and quinine (35 pmoles) on the mean number of spontaneous FR events (occurrence of FRs), as well as on the mean number of oscillation cycles per FR event and their frequency, were assessed using a specific algorithm to analyze FRs in intracranial EEG recordings. Results: We found that these gap junction blockers decreased the mean number of FRs and the mean number of oscillation cycles per FR event in the hippocampus, both during and at different times after carbenoxolone and quinine administration. Conclusion: These data suggest that FRs may be modulated by gap junctions, although additional experiments in vivo will be necessary to determine the precise role of gap junctions in this pathological activity associated with epileptogenesis.
    Full-text · Article · Sep 2014 · BioMed Research International
    • "It is now well-established, that in contrary to some epilepsy models (for example, treatment with KA or pilocarpine), when the appearance of degenerative changes is associated with the initial seizure responses (He et al., 2010; Kato et al., 1999), in the case of PTZ treatment, neurodegeneration is absent or appeared later. According to several scientists, epilepsy models associated with early neurodegeneration closely resemble the situation observed in patients with epilepsy. "

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    • "The lack of observed seizure activity in young mice would support the hypothesis that mutation of Elfn1 may set into motion long-term epileptogenic processes that eventually lead to a seizure-prone brain [67]. Finally, Elfn1 is also expressed in subsets of interneurons in the hilus as well as in the neocortex and piriform cortex, and strongly in the dorsal subiculum, regions also known to exhibit epileptogenic activity [68], [69], [70]. "
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    ABSTRACT: A growing number of proteins with extracellular leucine-rich repeats (eLRRs) have been implicated in directing neuronal connectivity. We previously identified a novel family of eLRR proteins in mammals: the Elfns are transmembrane proteins with 6 LRRs, a fibronectin type-3 domain and a long cytoplasmic tail. The recent discovery that Elfn1 protein, expressed postsynaptically, can direct the elaboration of specific electrochemical properties of synapses between particular cell types in the hippocampus strongly reinforces this hypothesis. Here, we present analyses of an Elfn1 mutant mouse line and demonstrate a functional requirement for this gene in vivo. We first carried out detailed expression analysis of Elfn1 using a β-galactosidase reporter gene in the knockout line. Elfn1 is expressed in distinct subsets of interneurons of the hippocampus and cortex, and also in discrete subsets of cells in the habenula, septum, globus pallidus, dorsal subiculum, amygdala and several other regions. Elfn1 is expressed in diverse cell types, including local GABAergic interneurons as well as long-range projecting GABAergic and glutamatergic neurons. Elfn1 protein localises to axons of excitatory neurons in the habenula, and long-range GABAergic neurons of the globus pallidus, suggesting the possibility of additional roles for Elfn1 in axons or presynaptically. While gross anatomical analyses did not reveal any obvious neuroanatomical abnormalities, behavioural analyses clearly illustrate functional effects of Elfn1 mutation. Elfn1 mutant mice exhibit seizures, subtle motor abnormalities, reduced thigmotaxis and hyperactivity. The hyperactivity is paradoxically reversible by treatment with the stimulant amphetamine, consistent with phenotypes observed in animals with habenular lesions. These analyses reveal a requirement for Elfn1 in brain function and are suggestive of possible relevance to the etiology and pathophysiology of epilepsy and attention-deficit hyperactivity disorder.
    Full-text · Article · Nov 2013 · PLoS ONE
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