title: Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain.
abstract: Severe head trauma causes widespread neuronal shear injuries and acute seizures. Shearing of neural processes might contribute to seizures by disrupting the transmembrane ion gradients that subserve normal synaptic signaling. To test this possibility, we investigated changes in intracellular chloride concentration ([Cl(-)](i)) associated with the widespread neural shear injury induced during preparation of acute brain slices. In hippocampal slices and intact hippocampal preparations from immature CLM-1 mice, increases in [Cl(-)](i) correlated with disruption of neural processes and biomarkers of cell injury. Traumatized neurons with higher [Cl(-)](i) demonstrated excitatory GABA signaling, remained synaptically active, and facilitated network activity as assayed by the frequency of extracellular action potentials and spontaneous network-driven oscillations. These data support a more inhibitory role for GABA in the unperturbed immature brain, demonstrate the utility of the acute brain slice preparation for the study of the consequences of trauma, and provide potential mechanisms for both GABA-mediated excitatory network events in the slice preparation and early post-traumatic seizures.
authors.affiliation: Department of Neurology, Harvard Medical School, Boston, MA, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Dzhala
authors.forename: Guzel
authors.initials: G
authors.lastname: Valeeva
authors.forename: Joseph
authors.initials: J
authors.lastname: Glykys
authors.forename: Rustem
authors.initials: R
authors.lastname: Khazipov
authors.forename: Kevin
authors.initials: K
authors.lastname: Staley
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000954:Antigens, Surface / Q000235:genetics; D001930:Brain Injuries / Q000473:pathology*; D002034:Bumetanide / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D002794:Choline / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D006801:Humans; D021621:Imaging, Three-Dimensional; D066298:In Vitro Techniques; D008164:Luminescent Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009415:Nerve Net / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012044:Regression Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013844:Thiazoles / Q000494:pharmacology; D013864:Thioglycolates / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000954:Antigens, Surface; C444139:CD300C protein, human; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; C572191:N-(4-methylthiazol-2-yl)-2-(6-phenylpyridazin-3-ylthio)acetamide; D010721:Phosphinic Acids; D011412:Propanolamines; D011993:Recombinant Fusion Proteins; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013844:Thiazoles; D013864:Thioglycolates; C415371:clomeleon; D002034:Bumetanide; C085075:CGP 55845A; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D020169:Caspases; D014633:Valine; D002794:Choline