Abstract
Febrile seizures are the most common type of developmental seizures, affecting up to 5% of children. Experimental complex febrile seizures involving the immature rat hippocampus led to a persistent lowering of seizure threshold despite an upregulation of inhibition. Here we provide a mechanistic resolution to this paradox by showing that, in the hippocampus of rats that had febrile seizures, the long-lasting enhancement of the widely expressed intrinsic membrane conductance Ih converts the potentiated synaptic inhibition to hyperexcitability in a frequency-dependent manner. The altered gain of this molecular inhibition-excitation converter reveals a new mechanism for controlling the balance of excitation-inhibition in the limbic system. In addition, here we show for the first time that h-channels are modified in a human neurological disease paradigm.
Highlights
H-channels are present in both cardiac and neuronal tissues, and play important functional roles, including the generation of the pacemaker current in the heart and sleep rhythms in thalamo-cortical neuronal circuits[12,13,14,15,16]
Using a novel rat model of complex febrile seizures[9,10], we have previously shown that prolonged hyperthermiainduced seizures at postnatal day 10 (P10) lead to a persistent increase in perisomatic inhibition of CA1 pyramidal neurons in the rat hippocampus[5]
A train of inhibitory postsynaptic potentials (IPSPs) triggered post-inhibitory rebound depolarization and firing in cells from hyperthermia-induced seizures (HT) rats (Fig. 3d and e; control, n = 7; HT, n = 7; there is no change in the threshold for action potential generation[5]; the reversal potential for inhibitory post synaptic currents (IPSCs) is unaltered: control, −58.2 ± 1.7 mV, n = 6; HT, −60.1 ± 1.6 mV, n = 7)
Summary
H-channels are present in both cardiac and neuronal tissues, and play important functional roles, including the generation of the pacemaker current in the heart and sleep rhythms in thalamo-cortical neuronal circuits[12,13,14,15,16]. Whole-cell recordings indicated that the selective hchannel blocker ZD-7288 (100 μM)[16,21] caused a larger hyperpolarization of Vm in cells from HT animals (control, 4.0 ± 1.0 mV, n = 6; HT, 7.3 ± 0.7mV, n = 8) These results are consistent with a more active Ih in cells from experimental animals even at potentials close to rest (Fig. 1). Single IPSPs did not evoke rebound depolarization or firing in either control or experimental animals (Fig. 3d, inset). A train of IPSPs triggered post-inhibitory rebound depolarization and firing in cells from HT rats (Fig. 3d and e; control, n = 7; HT, n = 7; there is no change in the threshold for action potential generation[5]; the reversal potential for IPSCs is unaltered: control, −58.2 ± 1.7 mV, n = 6; HT, −60.1 ± 1.6 mV, n = 7).
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