cgp-55845a 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

The hypothesis that plastic changes in the efficacy of excitatory neurotransmission occur in areas of chronic cortical injury was tested by assessing short-term plasticity of evoked excitatory synaptic currents (EPSCs) in neurons of partially isolated neocortical islands (undercut cortex). Whole cell recordings were obtained from layer V pyramidal neurons of sensorimotor cortical slices prepared from P36-P43 control and undercut rats. AMPA/kainate receptor-mediated EPSCs elicited by stimuli delivered at 40 to 66.7 Hz exhibited more paired-pulse depression (PPD) in undercut cortex than control, the time constant of depression evoked by trains of 20- to 66.7-Hz stimuli was faster, and the steady-state amplitude of EPSCs reached after five to seven EPSCs was lower. An antagonist of the glutamate autoreceptor, group II mGluR, increased the steady-state amplitude of EPSCs from undercut but not control cortex, suggesting that activation of presynaptic receptors by released glutamate is more prominent in undercut cortex. In contrast, the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid had no effect. Increasing [Ca(2+)](o) from 2 to 4 mM increased PPD, with a smaller effect in neurons of the undercut. The I-V relationship of AMPA/kainate receptor-mediated EPSCs was close to linear in both control and undercut neurons, and spermine had no significant effect on the EPSCs, suggesting that decreases in postsynaptic glutamate receptors containing the GluR2 subunit were not involved in the alterations in short-term plasticity. Results are compatible with an increase in the probability of transmitter release at excitatory synapses in undercut cortex due to functional changes in presynaptic terminals.

Topics: Animals; Animals, Newborn; Bicuculline; Brain Injuries; Calcium; Cerebral Cortex; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; In Vitro Techniques; Neural Inhibition; Neuronal Plasticity; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Synapses