Article

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: 4.35). 03/2009; 20(1):80-95. DOI: 10.1111/j.1750-3639.2009.00243.x
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Anatol Bragin, Jul 04, 2015
0 Followers
 · 
100 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the normal mammalian brain, neuronal synchrony occurs on a spatial scale of submillimeters to centimeters and temporal scale of submilliseconds to seconds that is reflected in the occurrence of high-frequency oscillations, physiological sharp waves and slow wave sleep oscillations referred to as Up-Down states. In the epileptic brain, the well-studied pathologic counterparts to these physiological events are pathological high-frequency oscillations and interictal spikes that could be electrophysiological biomarkers of epilepsy. Establishing these abnormal events as biomarkers of epilepsy will largely depend on a better understanding of the mechanisms underlying their generation, which will not only help distinguish pathological from physiological events, but will also determine what roles these pathological events play in epileptogenesis and epileptogenicity. This article focuses on the properties and neuronal mechanisms supporting the generation of high-frequency oscillations and interictal spikes, and introduces a new phenomenon called Up-spikes.
    Biomarkers in Medicine 10/2011; 5(5):545-56. DOI:10.2217/bmm.11.72 · 2.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Temporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary brain injury occurred a long time before the appearance of neurological symptoms. This type of epilepsy is characterized by refractoriness to drug treatment, so to require treatment with surgical resection of mesial temporal regions involved in seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor and channel functioning and modifications in other cellular components. In particular, a growing body of evidence from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive therapies.
    Current Medicinal Chemistry 11/2013; 21. DOI:10.2174/0929867320666131119152201 · 3.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 11/2013; 8(11):e80491. DOI:10.1371/journal.pone.0080491 · 3.53 Impact Factor