Persistently Decreased Basal Synaptic Inhibition of Hippocampal CA1 Pyramidal Neurons after Neonatal Hypoxia-Induced Seizures

Abstract

Hypoxia is the most common cause of neonatal seizures and can lead to epilepsy, but the epileptogenic mechanisms are not yet understood. We have previously shown that hypoxia-induced seizures in the neonatal rat result in acutely decreased amplitudes and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in hippocampal CA1 pyramidal neurons. In the current study, we asked whether such changes persist for several days following hypoxia-induced seizures. Similar to the acute findings, we observed decreased frequency and amplitudes of sIPSCs and decreased mIPSC amplitudes in CA1 pyramidal neurons at 3–5 days after hypoxia. However, in contrast to the acute findings, we observed no differences between hypoxia-treated and control groups in mIPSC frequency. Additionally, by 7 days after hypoxia, sIPSC amplitudes in the hypoxia group had recovered to control levels, but sIPSC frequency remained decreased. These data indicate that the persistently decreased sIPSC frequency result from decreased firing of presynaptic inhibitory interneurons, with only transient possible changes in postsynaptic responses to GABA release.

Prenatal hypoxia down regulates the GABA pathway in newborn mice cerebral cortex; partial protection by MgSO4

“…All of the above suggests that the decreased GAD levels and GAD65/VGAT ratios present in the cerebral cortex 24 h after prenatal hypoxia may increase the risk for subsequent seizure activity. The report of a lower frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSC) in newborn rats after hypoxia‐induced seizures supports the hypothesis that there are hypoxia‐induced deficiencies in presynaptic mechanisms (Sanchez et al, 2007).…”

Enhanced Integration of Newborn Neurons after Neonatal Insults

“…Although hypoxia in P10–12 rats induces acute behavioral seizure activity (Jensen et al, 1991b; Yang et al, 2004), we did not observe behavioral seizures in hypoxia-treated mouse pups. Furthermore, we did not detect a reduction in sIPSCs in CA1 pyramidal cells as was reported in neonatal rats following hypoxia-induced seizures (Sanchez et al, 2007). Species-specific differences in development or seizure response could underlie these discrepancies.…”

“…To further examine potential changes in network activity, we also examined sIPSCs in CA1 pyramidal cells in control and hypoxia-treated mice. Febrile or hypoxia-induced seizures in P10 rats can increase or decrease, respectively, the frequency of sIPSCs in CA1 pyramidal cells 1 week following seizure induction (Chen et al, 1999; Sanchez et al, 2007). However, using depolarized recording conditions that allow detection of sIPSCs without blocking glutamatergic transmission, we found no difference in sIPSCs after our hypoxia treatment in mice (Figure 3C).…”

“…We used a model developed for hypoxia-induced seizures in rats (Jensen et al, 1991b; Koh et al, 2004; Sanchez et al, 2007). Briefly, pups at P10 were placed in an airtight chamber on heating pads.…”

Downregulation of Hippocampal GABA after Hypoxia-Induced Seizures in Neonatal Rats

“…Efforts to understand the mechanism of hypoxia-induced neonatal epilepsy have been focused on the function and expression of GABA and its receptor. Sanchez et al [8,9] reported that hypoxia-induced seizures in the immature brain resulted in immediate and persistent decreases in GABAergic synaptic inhibition of hippocampal cornu Ammonis (CA) 1 pyramidal neurons. However, a number of recent studies have demonstrated that the release of GABA in early development of the CNS can increase the Ca 2?…”