Hyperosmolar therapy reduces neocortical epileptiform activity in vitro at a clinically relevant dose during early development
Abstract number :
1.021
Submission category :
1. Translational Research: 1A. Mechanisms / 1A4. Mechanisms of Therapeutic Interventions
Year :
2017
Submission ID :
340333
Source :
www.aesnet.org
Presentation date :
12/2/2017 5:02:24 PM
Published date :
Nov 20, 2017, 11:02 AM
Authors :
Joseph Glykys, Massachusetts General Hospital/Harvard Medical School; Elizabeth Duquette, Massachusetts General Hospital/Northeastern University; and Kevin Staley, Massachusetts General Hospital/Harvard Medical School
Rationale: The modulation of intraneuronal Cl- ([Cl-]i) has clinical implications. A decrease in [Cl-]i improves the efficacy of anticonvulsant GABAA receptor modulators. Brain injury and acute seizures induce the accumulation of [Cl-]i in vitro. Movement of water and ions, including Cl-, are linked in neurons because these cells do not have aquaporins to move free water. Hyperosmolar therapy is commonly used to treat brain edema. We tested if hyperosmotic therapy with mannitol induces a decrease in epileptiform activity and neuronal [Cl-]i in the neocortex by using electrophysiological techniques and multiphoton imaging. Methods: Acute brain slices (post-natal day 7-12) and organotypic neocortical culture slices (days in vitro 7-8) were used to study the effect of a 20 mOsm increase in perfusion solution (by mannitol) on induced and spontaneous epileptiform activity, multi-unit activity and neuronal [Cl-]i in the neocortex. C57BL/6 and Clomeleon mice were used for these experiments. Results: We observed that an increase in extracellular osmolarity by mannitol led to: 1) A decrease in induced and spontaneous epileptiform activity. 2) A decrease in spontaneous multi-unit activity (MUA) frequency but not amplitude in the presence of excitatory neurotransmission block. 3) A decrease in neuronal [Cl-]i concentration. 4) A clinically relevant concentration of the GABAA receptor modulator diazepam had insignificant anticonvulsant effects until potentiated by 20 mM mannitol. Conclusions: We conclude that an increase in the extracellular osmolarity by mannitol leads to a decrease in epileptiform activity in the neocortex in vitro during early development and enhances benzodiazepine actions. Our results indicate that mannitol decreases neuronal [Cl-]i and enhances inhibitory actions of GABA at this early developmental age. Therapies aimed to decrease neuronal volume and [Cl-]i are another approach to treat seizures in the developing brain after acute injury. Funding: JG was supported by the NIH/NINDS K08 1K08NS091248. KS was supported by NIH/NINDS 5R01NS40109-14
Translational Research