Dysfunction of hippocampal interneurons in epilepsy.
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ABSTRACT:
SUBMITTER: Liu YQ
PROVIDER: S-EPMC5562563 | biostudies-other | 2014 Dec
REPOSITORIES: biostudies-other
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Project description:Profile of GABAergic interneuron activity after pilocarpine-induced status epilepticus (SE) was examined in the rat hippocampal dentate gyrus by analyzing immediate early gene expression and recording spontaneous firing at near resting membrane potential (REM). SE for exact 2 h or more than 2 h was induced in the male Sprague-Dawley rats by an intraperitoneal injection of pilocarpine. Expression of immediate early genes (IEGs) was examined at 1 h, 1 week, 2 weeks or more than 10 weeks after SE. For animals to be examined at 1 h after SE, SE lasted for exact 2 h was terminated by an intraperitoneal injection of diazepam. Spontaneous firing at near the REM was recorded in interneurons located along the border between the granule cell layer and the hilus more than 10 weeks after SE. Results showed that both c-fos and activity-regulated cytoskeleton associated protein (Arc) in hilar GABAergic interneurons were up-regulated after SE in a biphasic manner; they were increased at 1 h and more than 2 weeks, but not at 1 week after SE. Ten weeks after SE, nearly 60% of hilar GABAergic cells expressed c-fos. With the exception of calretinin (CR)-positive cells, percentages of hilar neuronal nitric oxide synthase (nNOS)-, neuropeptide Y (NPY)-, parvalbumin (PV)-, and somatostatin (SOM)-positive cells with c-fos expression are significantly higher than those of controls more than 10 weeks after SE. Without the REM to be more depolarizing and changed threshold potential level in SE-induced rats, cell-attached recording revealed that nearly 90% of hilar interneurons fired spontaneously at near the REM while only 22% of the same cell population did so in the controls. In conclusion, pilocarpine-induced SE eventually leads to a state in which surviving dentate GABAergic interneurons become hyperactive with a subtype-dependent manner; this implies that a fragile balance between excitation and inhibition exists in the dentate gyrus and in addition, the activity-dependent up-regulation of IEGs may underlie plastic changes seen in some types of GABAergic cells in the pilocarpine model of epilepsy.
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Project description:Postmortem studies have reported decreased density and decreased gene expression of hippocampal interneurons in bipolar disorder, but neuroimaging studies of hippocampal volume and function have been inconclusive.To assess hippocampal volume, neuron number, and interneurons in the same specimens of subjects with bipolar disorder and healthy control subjects.Whole human hippocampi of 14 subjects with bipolar disorder and 18 healthy control subjects were cut at 2.5-mm intervals and sections from each tissue block were either Nissl-stained or stained with antibodies against somatostatin or parvalbumin. Messenger RNA was extracted from fixed tissue and real-time quantitative polymerase chain reaction was performed.Basic research laboratories at Vanderbilt University and McLean Hospital.Brain specimens from the Harvard Brain Tissue Resource Center at McLean Hospital.Volume of pyramidal and nonpyramidal cell layers, overall neuron number and size, number of somatostatin- and parvalbumin-positive interneurons, and messenger RNA levels of somatostatin, parvalbumin, and glutamic acid decarboxylase 1.The 2 groups did not differ in the total number of hippocampal neurons, but the bipolar disorder group showed reduced volume of the nonpyramidal cell layers, reduced somal volume in cornu ammonis sector 2/3, reduced number of somatostatin- and parvalbumin-positive neurons, and reduced messenger RNA levels for somatostatin, parvalbumin, and glutamic acid decarboxylase 1.Our results indicate a specific alteration of hippocampal interneurons in bipolar disorder, likely resulting in hippocampal dysfunction.
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Project description:Although some physiological functions of kainate receptors (KARs) still remain unclear, recent advances have highlighted a role in synaptic physiology. In hippocampal slices, kainate depresses GABA-mediated synaptic inhibition and increases the firing rate of interneurons. However, the sensitivity to agonists of these responses differs, suggesting that the presynaptic and somatic KARs have a distinct molecular composition. Hippocampal interneurons express several distinct KAR subunits that can assemble into heteromeric receptors with a variety of pharmacological properties and that, in principle, could fulfill different roles. To address which receptor types mediate each of the effects of kainate in interneurons, we used new compounds and mice deficient for specific KAR subunits. In a recombinant assay, 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) acted exclusively on homomeric glutamate receptor subunit 5 (GluR5), whereas 3S,4aR,6S,8aR-6-((4-carboxyphenyl)methyl) 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) antagonized homomeric GluR5 and any heteromeric combination containing GluR5 subunits. In hippocampal slices, LY382884, but not NS3763, was able to prevent kainate-induced depression of evoked IPSC. In contrast, neither prevented the concomitant increase in spontaneous IPSC frequency. The selectivity of these compounds was seen additionally in knock-out mice, such that they were inactive in GluR5-/- mice but completely effective in GluR6-/- mice. Our data indicate that in wild-type mice, CA1 interneurons express heteromeric GluR6 -KA2 receptors in their somatic compartments and GluR5-GluR6 or GluR5-KA2 at presynaptic terminals. However, functional compensation appears to take place in the null mutants, a new pharmacological profile emerging more compatible with the activity of homomeric receptors in both compartments: GluR5 in GluR6-/- mice and GluR6 in GluR5-/- mice.
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