Mannitol decreases neocortical epileptiform activity during early brain development via cotransport of chloride and water

J Glykys; E Duquette; N Rahmati; K Duquette; K J Staley

doi:10.1016/j.nbd.2019.01.024

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Mannitol decreases neocortical epileptiform activity during early brain development via cotransport of chloride and water

Journal article

Peer reviewed

Mannitol decreases neocortical epileptiform activity during early brain development via cotransport of chloride and water

J Glykys, E Duquette, N Rahmati, K Duquette and K J Staley

Neurobiology of disease, Vol.125, pp.163-175

05/2019

DOI: 10.1016/j.nbd.2019.01.024

PMCID: PMC6459411

PMID: 30711483

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https://doaj.org/article/faadf5ef3e374beab7a23fbd3a298350View

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Abstract

Seizures and brain injury lead to water and Cl− accumulation in neurons. The increase in intraneuronal Cl− concentration ([Cl−]i) depolarizes the GABAA reversal potential (EGABA) and worsens seizure activity. Neocortical neuronal membranes have a low water permeability due to the lack of aquaporins necessary to move free water. Instead, neurons use cotransport of ions including Cl− to move water. Thus, increasing the extracellular osmolarity during seizures should result in an outward movement of water and salt, reducing [Cl−]i and improving GABAA receptor-mediated inhibition. We tested the effects of hyperosmotic therapy with a clinically relevant dose of mannitol (20 mM) on epileptiform activity, spontaneous multiunit activity, spontaneous inhibitory post-synaptic currents (sIPSCs), [Cl−]i, and neuronal volume in layer IV/V of the developing neocortex of C57BL/6 and Clomeleon mice. Using electrophysiological techniques and multiphoton imaging in acute brain slices (post-natal day 7–12) and organotypic neocortical slice cultures (post-natal day 14), we observed that mannitol: 1) decreased epileptiform activity, 2) decreased neuronal volume and [Cl−]i through CCCs, 3) decreased spontaneous multi-unit activity frequency but not amplitude, and 4) restored the anticonvulsant efficacy of the GABAA receptor modulator diazepam. Increasing extracellular osmolarity by 20 mOsm with hypertonic saline did not decrease epileptiform activity. We conclude that an increase in extracellular osmolarity by mannitol mediates the efflux of [Cl−]i and water through CCCs, which results in a decrease in epileptiform activity and enhances benzodiazepine actions in the developing neocortex in vitro. Novel treatments aimed to decrease neuronal volume may concomitantly decrease [Cl−]i and improve seizure control.

development

chloride

seizures

neocortex

GABA transmission

water

mannitol

cytotoxic edema

Details

Title: Subtitle: Mannitol decreases neocortical epileptiform activity during early brain development via cotransport of chloride and water
Creators: J Glykys - Department of Neurology, Massachusetts General Hospital, Boston, 02114
E Duquette - Department of Neurology, Massachusetts General Hospital, Boston, 02114
N Rahmati - Department of Neurology, Massachusetts General Hospital, Boston, 02114
K Duquette - Department of Neurology, Massachusetts General Hospital, Boston, 02114
K J Staley - Department of Neurology, Massachusetts General Hospital, Boston, 02114
Resource Type: Journal article
Publication Details: Neurobiology of disease, Vol.125, pp.163-175
DOI: 10.1016/j.nbd.2019.01.024
PMID: 30711483
PMCID: PMC6459411
NLM abbreviation: Neurobiol Dis
ISSN: 0969-9961
eISSN: 1095-953X
Grant note: name: NIH, award: 1K08NS091248; name: NIH, award: 5R01NS40109-14.
Language: English
Date published: 05/2019
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984014017102771

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