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Department
Physiology
Course
Physiology 4700A/B
Professor
Stan Leung
Semester
Fall

Description
Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy R. Cossart, C. Dinocourt, J. C. Hirsch, A. Merchan-Perez, J. De Felipe, Y. Ben-Ari, M. Esclapez and C. Bernard Presented by: Kira Misuraca & Gillian Finnie Note: the last section of the document illustrates the important neural circuits and briefly explains the application of TTX Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. It is a type of partial (focal) seizure that originates in the temporal lobe. Abnormalities of the temporal lobe are associated with vivid perception of colours and emotional responses because it has a strong connection with the limbic system mediated by the entorhinal cortex (EC) - remember: Van Gogh! Temporal lobe epilepsy is associated with neuronal cell loss and axonal sprouting in the hippocampus. Cossart et al. aimed to better characterize neuronal cell loss and GABAergic synapse reorganization in the hippocampus, primarily in the CA1 region. They used brain slices from rats exposed to kainate and pilocarpine, both excitatory agonists. Exposure to kainate or pilocarpine produces status epilepticus, which results spontaneous seizures after a latency period. Whole- and cell-attached recordings were taken to define the electrophysiological response in different subpopulations of interneurons and in pyramidal cells. The majority of interneurons in the hippocampus are inhibitory and act to modulate principal cell output. Two major interneuron classifications were described: dendritic-projecting (O-LM) and somatic projecting (from stratum pyramidale and radiatum). Interneurons in the stratum oriens that project to the stratum lacunosum (O-LM interneurons), where the distal dendrites of pyramidal cells are, were found to be largely reduced in experimental epilepsy. GAD67 and somatostatin staining for GABAergic neurons each revealed a huge decrease in the cells found in the s. oriens. Surviving somatostatin-expressing cells also expressed calbindin, identifying them as a subpopulation of interneurons that project to the medial septum. There was significant GABAergic cell death in the stratum oriens, with particular vulnerability of stratum lacunosum-projecting interneurons. Additionally, they observed a 38% decrease in the stratum lacunosum moleculare. To determine if cell loss was associated with a symmetrical synapse reduction, they compared the number of symmetric (inhibitory) and asymmetric (excitatory) synapses in control and experimental conditions. The density of synapses was comparable between conditions. Taking the 38% decrease of s. lacunosum moleculare into account, the density of symmetric synapses in experimental TLE was a 62% of control. The ratio of asymmetrical to symmetrical synapses in lacunosum moleculare increased by 46% in experimental animals (p<0.05), showing an increased excitation/inhibition ratio. The balance between excitation and inhibition determines principal cell firing. Since there was preferential cell death of O-LM interneurons, Cossart et al. split their analysis of interneurons into two groups: 1) stratum radiatum with s. pyramidale and 2) s. oriens. They also split analysis of pyramidal neurons into 3) dendritic and 4) somatic recordings. 1) Stratum radiatum and s. pyramidale interneurons:  82% fired spontaneously compared to 41% of control  Interneurons fired at a higher frequency in epileptic than in controls by 240% (p<0.05)  7-fold increase in sEPSCs from glutamatergic input (p<0.01) in experimental VS control 2) Stratum oriens projecting to s. lacunosum interneurons (O-LM) * used medial-projecting s. oriens interneurons (remember: co-expressing somatostatin and calbindin) because too few surviving O-LM interneurons to reliably record from potential limitation  increased spontaneous APs and EPSCs in experimental condition  stimulation of s. radiatum moleculare evoked a epileptiform response  higher percentage of cells in higher frequency group than in the control  sEPSCs in control condition greater than for s. radiatum and pyramidale interneurons o could suggest a greater role of O-LM neurons for inhibition ALL IDENTIFIED INTER
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