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Basic Science of Epilepsy

Tight Coupling of Astrocyte pH Dynamics to Epileptiform Activity Revealed by Genetically Encoded pH Sensors

Journal Neuroscience

Raimondo JV, Tomes H, Irkle A, Kay L, Kellaway L, Markram H, Millar RP, Akerman CJ
Contributed by Sloka S. Iyengar, PhD. Short title: pH changes in astrocytes in seizures
Journal of Neuroscience 2016 Jun 29;36(26):7002-13. doi: 10.1523/JNEUROSCI.0664-16.2016

Summary for non-specialists

Studies have shown that neuronal pH during a seizure tends towards acidification. However, since astrocytes are important regulators of ionic homeostasis in the brain, what happens to astrocytic pH during a seizure might provide important clues about seizure initiation and propagation. The authors used genetically encoded pH reporters in organotypic hippocampal slice cultures, and found that astrocytes become rapidly alkaline during a seizure-like event. Also, pH changes in astrocytes are more closely linked to network activity than neuronal pH changes, and this rapid alkalinization is mediated by Na+/HCO3- cotransporters. This study helps broaden our understanding of pH alterations and seizure dynamics.

High-gamma (HG; 80-150 Hz) activity in macroscopic clinical records is considered a marker for critical brain regions involved in seizure initiation; it is correlated with pathological multiunit firing during neocortical seizures in the seizure core, an area identified by correlated multiunit spiking and low frequency seizure activity. However, the effects of the spatiotemporal dynamics of seizure on HG power generation are not well understood. Here we studied HG generation and propagation, using a three-step, multiscale signal analysis and modeling approach.

First, we analyzed concurrent neuronal and microscopic neetwork HG activity in neocortical slices from seven intractable epilepsy patients. We found HG activity in these networks, especially when neurons displayed paroxyysmal depolarization shifts and network activity was highly synchronized. Second, we examined HG activity acquired with microelectrode arrays recorded during numan seizures (=8). We confirmed the presence of syncronized HG power across microelectrode records and the macroscale, both specifically associated with the core region of the seizure. Third, we used volume conduction-based modeling to relate HG activity and network synchrony at different network scalses. We showed that local HG oscillations require high levels of synchrony to cross scales, and that this requirement is met at the microscopic scale, but not within macroscopic networks. Instead, we present evidence that HG power at the macroscale may result from harmonics of ongoing seizure activity. Ictal HG power marks the seizure core, but the generating mechanism can differ across spatial scales.

Abstract


Reducing premature KCC2 expression rescues seizure susceptibility and spine morphology in atypical febrile seizures

Awad PN, Sanon NT, Chattopadhyaya B, Carriço JN, Ouardouz M, Gagné J, Duss S, Wolf D, Desgent S, Cancedda L, Carmant L, Di Cristo G
Contributed by Sloka S. Iyengar, PhD
Neurobiology of Disease, July 2016 91:10-20. doi: 10.1016/j.nbd.2016.02.014. Epub 2016 Feb 10.

Summary for non-specialists

Atypical febrile seizures are lateralized, prolonged and numerous; and can be a risk factor for epilepsy later in life. The link between cortical malformations, febrile seizures and epilepsy has been suggested, but the underlying mechanism isn’t fully understood. In this study, the scientists used a rat model (“LHS rats”) where cortical dysplasia and hyperthermia-induced seizures eventually lead to epilepsy and associated neurological sequelae. Given the role of KCC2 in GABAergic neurotransmission, they looked at expression and function of KCC2 in LHS rats. They found an increase in levels of KCC2 protein in these rats, a reduction in number of dendritic spines and abnormal dendritic maturation in area CA1 of the hippocampus. Reducing KCC2 protein expression using in-utero electroporation of shRNA reduced seizure number and corrected deficits in dendritic spines. Hence, alterations in KCC2 may be a common link between cortical dysplasia, febrile seizures and epilepsy.

Abstract


Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus

Epilepsia

Sivakumaran S and Maguire J
Contributed by Sloka S. Iyengar, PhD
Epilepsia Volume 7, Issue 52, pages 222-232, February 2016. DOI: 10.1111/epi.13270

Summary for non-specialists

GABAergic neurotransmission depends on KCC1 and NKCC2 Cl− co-transporters; a dysfunction in these co-transporters is seen in neonatal seizures. Bumetanide – a drug that blocks NKCC1 chloride cotransporters – has been shown to be beneficial in seizures in neonates. In the current study, the authors wanted to test whether bumetanide would be useful in status epilepticus (SE) by using brain slice electrophysiology and in vivo EEG experiments. Administration of bumetanide reduced seizure-like events induced by zero-Mg+², and in intact mice by administration of kainic acid. As seizures progressed, diazepam led to pharmacoresistance, which bumetanide was able to overcome. Hence, this study suggests that there might be a new indication of bumetanide in SE.

Abstract


Treatment during a vulnerable developmental period rescues a genetic epilepsy.

Nature Medicine logo

Marguet SL, Le-Schulte VT, Merseburg A, Neu A, Eichler R, Jakovcevski I, Ivanov A, Hanganu-Opatz IL, Bernard C, Morellini F, Isbrandt D.
Contributed by Sloka S. Iyengar, PhD
Nature Medicine; vol 21 no. 12, December 2015, pp 1436-1444. doi:10.1038/nm.3987

Summary for non-specialists

There is a greater incidence of epilepsy during the first few years of life as neurodevelopmental processes are still underway. The current strategy is to administer anti-epileptic drugs after seizures occur. The authors of a recent paper investigated whether administration of bumetanide – a diuretic that blocks the NKCC1 cation-chloride co-transporter and dampens down depolarization – would be effective as an anti-epileptogenic agent in a mouse model of mutated Kv7 K+ channels. Transient administration of bumetanide was able to correct structural and functional changes in the hippocampus in the mutant mice. This study raises the possibility of bumetanide as an anti-epileptogenic agent.

Abstract | Article


Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model

Brain journal

Brain; Sept 2015
Wright S, Hashemi K, Stasiak L, Bartram J, Lang B, Vincent A, Upton AL

Summary for non-specialists

NMDAR antibody encephalitis is characterized by psychiatric symptoms like psychosis, paranoia and violent behavior, and may be followed by seizures. This study was done to examine the epileptogenicity of NMDAR antibodies in C57BL/6 mice. Administration of the antibody (IgG) into the lateral ventricle by itself did not cause spontaneous seizures, but exacerbated susceptibility of acute seizures caused by PTZ. Immunohistochemistry to visualize bound IgG showed that levels of IgG bound to the left hippocampus were proportional to seizure severity. This suggests that the IgG binds to, and causes internalization of NMDARs in the hippocampus, possibly leading to enhanced acutes eizures in response to PTZ.

Abstract | PDF


Microglial ROS production in an electrical rat post-status epilepticus model of epileptogenesis

Neuroscience Letters Journal

Rettenbeck ML, von Rüden EL, Bienas S, Carlson R, Stein VM, Tipold A, Potschka H
Neuroscience Letters; July 2015

Summary for non-specialists

Microglia are thought to contribute to epilepsy because they change shape and release reactive oxygen species (ROS). Most studies looking at microglial ROS production in epilepsy have been done after administration of a chemoconvulsant like pilocarpine or kainic acid. In the current study, the authors studied microglial ROS in an electrical status epilepticus (SE) model in rats. Using immunophenotyping to first identify microglia, the authors found an increase in microglial ROS two days after SE but not during epileptogenesis or epilepsy. Hence, anti-inflammatory strategies for epilepsy might be beneficial if they target the initial phase.

Abstract | PDF


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