Abstracts

Transient ischemia facilitates neuronal chloride accumulation, severity of seizures and cell death

Abstract number : 3.022
Submission category : 1. Translational Research: 1A. Mechanisms / 1A4. Mechanisms of Therapeutic Interventions
Year : 2017
Submission ID : 349909
Source : www.aesnet.org
Presentation date : 12/4/2017 12:57:36 PM
Published date : Nov 20, 2017, 11:02 AM

Authors :
Thomas Blauwblomme, Universite Paris Descartes, Sorbonne Paris Cite; Volodymyr Dzhala, Massachusetts General Hospital and Harvard Medical School; Michelle Mail, Massachusetts General Hospital and Harvard Medical School; and Kevin Staley, Massachusetts Gen

Rationale: Hypoxia-ischemia may trigger or exacerbate seizure activity and status epilepticus; the two conditions together worsen clinical outcome and increase death (Ryvlin, Lancet 2015).  Significant alterations in neuronal ionic transport in recurrent seizures (Dzhala et al., J Neurosci 2010), chronically epileptic tissue (Huberfeld et al., J Neurosci 2007) and ischemia (Pond et al., J Neurosci 2006) raise the possibility that altered chloride homeostasis and GABA signaling significantly aggravate the both seizure activity and ischemia.  Methods: We determined the effect of transient 30 min hypoxia-glucose deprivation (OGD) on neuronal chloride concentration,  recurrent seizures activity and cell death in the organotypic hippocampal slice cultures (DIV10-20), an in vitro model of post-traumatic seizures (Berdichevsky et al., J Neurosci 2013).  Extracellular field potential recordings and two-photon imaging of genetically encoded chloride indicator Clomeleon were performed to monitor neuronal activity, intracellular chloride concentration ([Cl-]i) and neuronal cell death.  Results: We found that during 30 min OGD seizure activity was initially potentiated, but this was followed by suppression of recurrent seizures as well as a progressive increase in the steady-state [Cl-]i.  During reoxygenation, the neuronal steady-state chloride initially partially recovered, but subsequently there was a secondary progressive neuronal chloride accumulation. The secondary phase of [Cl-]i  accumulation was associated with  recovery, potentiation and increased frequency of epileptiform discharges. Bumetanide, a sodium-potassium-chloride (NKCC1) co-transporter blocker, prevented neuronal chloride accumulation during and after recovery from OGD, but did not suppress recurrent high-frequency inter-ictal epileptiform discharges.   Conclusions: Our results demonstrate that transient ischemia strongly facilitates seizures. NKCC1 contributes to ischemia induced steady-state [Cl-]i  accumulation and  potentiation of recurrent seizures during  recovery from ischemia.     Funding: KS (NIH/NINDS RO1)TB (Research Grant from French Society of Neurosurgery)
Translational Research