Hippocampal inhibitory interneurons are functionally disconnected from excitatory inputs by anoxia

Abstract

1. The effects of anoxia on inhibitory synaptic transmission were studied in hippocampal slices of 3- to 4-wk-old rats. CA1 pyramidal cells were examined by whole-cell patch-clamp recording. Synaptic currents were evoked by "distant" (> 0.5 mm) or "close" (< 0.5 mm) electrical stimulation in the stratum radiatum. 2. The excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) evoked by distant stimulation were completely suppressed by brief anoxia (95% N2-5% CO2 for 4-6 min) and recovered upon reoxygenation. IPSCs were more sensitive to anoxia than EPSCs. EPSCs and IPSCs evoked by distant stimulation were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 20 microM) and D-2-amino-5-phosphonopentanoate (APV; 50 microM). This indicates that IPSCs were mediated via a polysynaptic pathway that involves glutamate receptors. 3. Synaptic currents evoked by close stimulation were only partly inhibited by anoxia. The bicuculline-sensitive gamma-aminobutyric acid-A (GABAA) receptor-mediated synaptic currents were particularly resistant to anoxia, suggesting that the GABAergic input to pyramidal neurons is not inhibited by anoxia. 4. At close stimulation in the stratum radiatum, monosynaptic IPSCs could be evoked in the presence of CNQX (20 microM) and APV (50 microM). The monosynaptic IPSCs had early bicuculline (15 microM) and late CGP 35348 (100 microM)-sensitive components confirming an involvement of GABAA and GABAB receptors (IPSCA and IPSCB components), respectively. 5. The monosynaptic IPSCA component evoked by close stimulation was not changed significantly during and after brief anoxia. Responses to pressure application of isoguvacine (GABAA agonist) were also not affected by anoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in Intracellular Chloride after Oxygen–Glucose Deprivation of the Adult Hippocampal Slice: Effect of Diazepam

“…It is unlikely that the decrease in MEQ fluorescence was already maximal after OGD, thereby preventing any additional decrease in MEQ fluorescence by muscimol; other compounds such as NMDA produce even greater decreases in MEQ fluorescence than reported here (Inglefield and SchwartzBloom, 1998b). Other investigators have reported that GABA Amediated inhibition is suppressed immediately after anoxia in the hippocampal slice, because of a loss of excitatory input onto GABA-ergic interneurons (Krnjević et al, 1991;Khazipov et al, 1993). In contrast, Katchman et al (1994) proposed that the loss of GABA A -mediated inhibition immediately after anoxia was attributable to a decrease in extracellular Cl Ϫ .…”

Ischemic Cerebral Damage

“…109,46 The inhibition is caused by failure of the excitatory input to inhibitory interneurons, leading to silencing of inhibitory interneurons. 110 This may contribute to excitotoxicity with delayed cell death. Also, it may lead to abnormal excitatory synchronicity after cerebral ischemia, manifesting as electroencephalographic status epilepticus in posthypoxic encephalopathy after cardiac arrest.…”

Run‐down of the GABAA response under experimental ischaemia in acutely dissociated CA1 pyramidal neurones of the rat.

“…In brain slice preparations, the evoked inhibitory postsynaptic current (IPSC; possibly polysynaptic) was suppressed under ischaemic conditions and was more sensitive to hypoxic insults than the evoked excitatory postsynaptic current (EPSC; Rosen & Morris, 1993). Recent findings suggest that the polysynaptic IPSC was sensitive to anoxia because excitatory input to the inhibitory interneurones are sensitive to it, while the monosynaptic IPSC is robust (Khazipov, Bregestovski & Ben-Ari, 1993). The monosynaptic GABAA receptor-mediated IPSC in CAl pyramidal neurones of the 3-to 4-week-old rat hippocampal slice was insensitive to anoxia, whereas the monosynaptic GABAB receptor-mediated IPSC was highly sensitive to the postsynaptic mechanism (Khazipov et al 1993).…”

“…Recent findings suggest that the polysynaptic IPSC was sensitive to anoxia because excitatory input to the inhibitory interneurones are sensitive to it, while the monosynaptic IPSC is robust (Khazipov, Bregestovski & Ben-Ari, 1993). The monosynaptic GABAA receptor-mediated IPSC in CAl pyramidal neurones of the 3-to 4-week-old rat hippocampal slice was insensitive to anoxia, whereas the monosynaptic GABAB receptor-mediated IPSC was highly sensitive to the postsynaptic mechanism (Khazipov et al 1993). However, intracellular recording from CAl pyramidal neurones of the adult rat hippocampal slice showed a suppression (38-2 %) of monosynaptic GABAA-mediated IPSC, possibly by way of some postsynaptic effects (Zhu & Krnjevic, 1994).…”