Decreased A‐currents in hippocampal dentate granule cells after seizure‐inducing hypoxia in the immature rat

Abstract

Purpose Cerebral hypoxia is a major cause of neonatal seizures, and can lead to epilepsy. Pathological anatomical and physiological changes in the dentate gyrus have been associated with epileptogenesis in many experimental models, as this region is widely believed to gate the propagation of limbic seizures. However, the consequences of hypoxia-induced seizures for the immature dentate gyrus have not been extensively examined. Methods Seizures were induced by global hypoxia (5–7% O2 for 15 minutes) in rat pups on postnatal day 10. Whole-cell voltage-clamp recordings were used to examine A-type potassium currents (IA) in dentate granule cells in hippocampal slices obtained 1–17 days after hypoxia treatment. Key Findings Seizure-inducing hypoxia resulted in decreased maximum IA amplitude in dentate granule cells recorded within the first week but not at later times after hypoxia treatment. The decreased IA amplitude was not associated with changes in the voltage-dependence of activation or inactivation removal, or in sensitivity to inhibition by 4-aminopyridine (4-AP). However, consistent with the role of IA in shaping firing patterns, we observed in the hypoxia group a significantly decreased latency to first spike with depolarizing current injection from hyperpolarized potentials. These differences were not associated with changes in resting membrane potential or input resistance, and were eliminated by application of 10 mM 4-AP. Significance Given the role of IA to slow action potential firing, decreased IA could contribute to long-term hippocampal pathology after neonatal seizure-inducing hypoxia by increasing DG cell excitability during a critical window of activity-dependent hippocampal maturation.

Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons

“…Microdialysis studies detected glutamate release in response to preterm fetal ovine HI, and glutamate receptor blockade rendered partial neuroprotection after severe preterm HI . Disturbances in glutamatergic signaling and excitatory synaptic transmission have been defined in rodents in response to neonatal hypoxia and seizures . It will thus be important to determine when such changes in synaptic signaling begin during fetal development and how long they persist, and to define the mechanisms that trigger and mediate such changes.…”

A physiologically-validated rat model of term birth asphyxia with seizure generation after, not during, brain hypoxia

“…By definition, asphyxia is a combination of systemic hypoxia and hypercapnia, and these two components of asphyxia have distinct -often functionally opposite -actions on the brain. Indeed, while hypoxia as such is known to promote neuronal excitability and seizures (Kawasaki et al, 1990;Jensen et al, 1991;Peng et al, 2013;Sampath et al, 2014;Zanelli et al, 2014 and references below), an elevation of systemic CO 2 produces a fall in brain pH and a consequent decrease in neuronal excitability (Lee et al, 1996;Pasternack et al, 1996;Ruusuvuori and Kaila, 2014;Schuchmann et al, 2006;Shi et al, 2017;Tolner et al, 2011).…”

Endogenous responses in brain pH andPO2in a rodent model of birth asphyxia

“…[29][30][31] This notion gets further impact in the context of BA from observations that experimental hypoxia as such (i.e., not as a component of asphyxia) leads to a gross increase in neuronal network excitability as has been shown in both in vivo and in vitro conditions. [32][33][34][35][36] "Pure" hypoxia, i.e. hypoxia without simultaneous hypercapniawhich never takes place in natural conditionshas dominated thinking not only in translational research of hypoxic-ischemic brain damage (see Discussion) but also in clinical practice, particularly regarding methods of resuscitation.…”