Early ischemia enhances action potential-dependent, spontaneous glutamatergic responses in CA1 neurons.
Two types of quantal spontaneous neurotransmitter release are present in the nervous system, namely action potential (AP)-dependent release and AP-independent release. Previous studies have identified and characterized AP-independent release during hypoxia and ischemia. However, the relative contribution of AP-dependent spontaneous release to the overall glutamate released during transient ischemia has not been quantified. Furthermore, the neuronal activity that mediates such release has not been identified. Using acute brain slices, we show that AP-dependent release constitutes approximately one-third of the overall glutamate-mediated excitatory postsynaptic potentials/currents (EPSPs/EPSCs) measured onto hippocampal CA1 pyramidal neurons. However, during transient (2 mins) in vitro hypoxia-hypoglycemia, large-amplitude, AP-dependent spontaneous release is significantly enhanced and contributes to 74% of the overall glutamatergic responses. This increased AP-dependent release is due to hyper-excitability in the presynaptic CA3 neurons, which is mediated by the activity of NMDA receptors. Spontaneous glutamate release during ischemia can lead to excitotoxicity and perturbation of neural network functions.
Department of Physiology, Toronto Western Research Institute, University Health Network, Room 13-411, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. hye@uhnresearch.ca
Hui
H
Ye
Shirin
S
Jalini
Liang
L
Zhang
Milton
M
Charlton
Peter L
PL
Carlen
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005971:Glutamates / Q000502:physiology*; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018808:Transcription Factor AP-1; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate