Abstracts

A-type K⁺ channels can critically determine neuronal excitability and shape spiking patterns. Pharmacological blockade of A-type currents (I[sub]A[/sub]) induces limbic seizures (Juhng et al., 1999 Epilepsy Res 23:675), and decreased or absent I[sub]A[/sub] in principal hippocampal neurons may promote seizures in multiple epilepsy models (Bernard, et al., 2004 Science 305:532; Castro, et al., 2001 J Neurosci 21: 6626). Hypoxia is a major cause of neonatal encephalopathy and seizures, and can lead to epilepsy, but the consequences of an acute episode of seizure-inducing hypoxia are not fully understood. In the current study, we asked whether I[sub]A[/sub] may be altered in hippocampal neurons following neonatal seizure-inducing hypoxia. We examined this in dentate granule cells, as the dentate gyrus is widely believed to gate the propagation of limbic seizures., Spontaneous seizures were induced by global hypoxia in P10 Long-Evans rat pups (5-7%O[sub]2[/sub] for 15 min; rectal temp. maintained at 33-34 deg. C.). Whole-cell voltage- and current-clamp recordings were obtained from visually identified dentate gyrus granule cells in hippocampal slices excised 30 min to 7 days post-hypoxia. The magnitude and voltage-dependence of I[sub]A[/sub], and spiking behavior was compared between control and hypoxia-treated groups., I[sub]A[/sub] was observed in all recorded dentate granule cells (n=57 control; n=79 hypoxia). In the hypoxia-treated group, I[sub]A[/sub] amplitude was decreased to 61% of control at maximal activation with no change in the voltage-dependence of activation or steady-state inactivation. Under current-clamp, depolarizing current injection from near rest (-60 to -65 mV) elicited similar spike patterns between the two groups. However, depolarizing steps to the same absolute current from a negative conditioning potential (-80 mV) to partially remove steady-state I[sub]A[/sub] inactivation revealed a longer delay to initial spike onset in the control (51[plusmn]3 ms) compared to the hypoxia-treated (15[plusmn]1 ms) group. This decreased spike latency also was associated with an increased spike frequency in the hypoxia-treated group under this experimental condition. No clear time-dependent differences were observed across days post-hypoxia., Our data indicated that I[sub]A[/sub] was decreased in dentate granule cells acutely and for at least one week following perinatal seizure-inducing hypoxia. Additionally, this decrease in I[sub]A[/sub] was associated with an increased propensity for more rapid action potential firing in response to depolarization from hyperpolarization within a physiological range. Given that the dentate gyrus is widely believed to gate the propagation of limbic epileptiform activity, the observed decrease in I[sub]A[/sub] may decrease this gating function by increasing the intrinsic excitability of dentate granule cells., (Supported by an EFA Postdoctoral Research Training Fellowship (BP) and PHS Grant NS 047385 (RMS).)