ABSTRACT
BACKGROUND AND PURPOSE: We investigated the contribution of gap junctions to brain damage and delayed neuronal death produced by oxygen-glucose deprivation (OGD). METHODS: Histopathology, molecular biology, and electrophysiological and fluorescence cell death assays in slice cultures after OGD and in developing rats after intrauterine hypoxia-ischemia (HI). RESULTS: OGD persistently increased gap junction coupling and strongly activated the apoptosis marker caspase-3 in slice cultures. The gap junction blocker carbenoxolone applied to hippocampal slice cultures before, during, or 60 minutes after OGD markedly reduced delayed neuronal death. Administration of carbenoxolone to ischemic pups immediately after intrauterine HI prevented caspase-3 activation and dramatically reduced long-term neuronal damage. CONCLUSIONS: Gap junction blockade may be a useful therapeutic tool to minimize brain damage produced by perinatal and early postnatal HI.
Subject(s)
Brain/embryology , Gap Junctions/metabolism , Glucose/metabolism , Ischemia/pathology , Neuroprotective Agents/metabolism , Animals , Anti-Ulcer Agents/pharmacology , Apoptosis , Carbenoxolone/pharmacology , Caspase 3 , Caspases/metabolism , Cell Communication , Connexins/metabolism , DNA/chemistry , Disease Models, Animal , Electrophysiology , Female , Hippocampus/metabolism , Hippocampus/pathology , Hypoxia/pathology , Hypoxia-Ischemia, Brain/pathology , Male , Mice , Mice, Inbred C57BL , Microscopy, Fluorescence , Nerve Degeneration , Neurons/metabolism , Nucleosomes/metabolism , Oxygen/chemistry , Polymerase Chain Reaction , Propidium/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
Deprivation-induced plasticity of sensory cortical maps involves long-term potentiation (LTP) and depression (LTD) of cortical synapses, but how sensory deprivation triggers LTP and LTD in vivo is unknown. Here we tested whether spike timing-dependent forms of LTP and LTD are involved in this process. We measured spike trains from neurons in layer 4 (L4) and layers 2 and 3 (L2/3) of rat somatosensory cortex before and after acute whisker deprivation, a manipulation that induces whisker map plasticity involving LTD at L4-to-L2/3 (L4-L2/3) synapses. Whisker deprivation caused an immediate reversal of firing order for most L4 and L2/3 neurons and a substantial decorrelation of spike trains, changes known to drive timing-dependent LTD at L4-L2/3 synapses in vitro. In contrast, spike rate changed only modestly. Thus, whisker deprivation is likely to drive map plasticity by spike timing-dependent mechanisms.
