n-(4-methylthiazol-2-yl)-2-(6-phenylpyridazin-3-ylthio)acetamide and Brain-Injuries

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.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Age Factors; Animals; Animals, Newborn; Antigens, Surface; Brain Injuries; Bumetanide; Caspases; Cell Count; Choline; Excitatory Amino Acid Antagonists; Female; GABA Antagonists; gamma-Aminobutyric Acid; Hippocampus; Humans; Imaging, Three-Dimensional; In Vitro Techniques; Luminescent Proteins; Male; Membrane Glycoproteins; Mice; Mice, Transgenic; Microscopy, Confocal; Nerve Net; Neurons; Phosphinic Acids; Propanolamines; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins; Regression Analysis; Signal Transduction; Sodium Potassium Chloride Symporter Inhibitors; Statistics, Nonparametric; Thiazoles; Thioglycolates; Time Factors; Valine