THE PRO-CONVULSANT ACTIONS OF CORTICOTROPIN-RELEASING HORMONE IN THE HIPPOCAMPUS OF INFANT RATS

Whole-cell patch-clamp and extracellular held recordings were obtained from 450-mu m-thick brain slices of infant rats (10-13 days postnatal ) to determine the actions of corticotropin-releasing hormone on gluta mate-and GABA-mediated synaptic transmission in the hippocampus. Synth etic corticotropin-releasing hormone (0.15 mu M) reversibly increased the excitability of hippocampal pyramidal cells, as determined by the increase in the amplitude of the CA1 population spikes evoked by stimu lation of the Schaffer collateral pathway. This increase in population spike amplitude could be prevented by the corticotropin-releasing hor mone receptor antagonist a-helical (9-41)-corticotropin-releasing horm one (10 mu M). Whole-cell patch-clamp recordings revealed that, in the presence of blockers of fast excitatory and inhibitory synaptic trans mission, corticotropin-releasing hormone caused only a small (1-2 mV) depolarization of the resting membrane potential in CA3 pyramidal cell s, and it did not significantly alter the input resistance. However, c orticotropin-releasing hormone, in addition to decreasing the slow aft erhyperpolarization, caused an increase in the number of action potent ials per burst evoked by depolarizing current pulses. Corticotropin-re leasing hormone did not significantly change the frequency, amplitude or kinetics of miniature excitatory postsynaptic currents. However, it increased the frequency of the spontaneous excitatory postsynaptic cu rrents in CA3 pyramidal cells, without altering their amplitude and si ngle exponential rise and decay time constants. Corticotropin-releasin g hormone did not change the amplitude of the pharmacologically isolat ed (1.9. recorded in the presence of GABA(A) receptor antagonist bicuc ulline) excitatory postsynaptic currents in CA3 and CA1 pyramidal cell s evoked by stimulation of the mossy fibers and the Schaffer collatera ls, respectively. Current-clamp recordings in bicuculline-containing m edium showed that, in the presence of corticotropin-releasing hormone, mossy fiber stimulation leads to large, synchronized, polysynapticall y-evoked bursts of action potentials in CA3 pyramidal cells. In additi on, the peptide caused a small, reversible decrease in the amplitude o f the pharmacologically isolated (i.e. recorded in the presence of glu tamate receptor antagonists) evoked inhibitory postsynaptic currents i n CA3 pyramidal cells, but it did not significantly alter the frequenc y, amplitude, rise and decay time constants of spontaneous or miniatur e inhibitory postsynaptic currents. These data demonstrate that cortic otropin-releasing hormone, an endogenous neuropeptide whose intracereb roventricular infusion results in seizure activity in immature rats, h as diverse effects in the hippocampus which may contribute to epilepto genesis. It is proposed that the net effect of corticotropin-releasing hormone is a preferential amplification of those incoming excitatory signals which are strong enough to reach firing threshold in at least a subpopulation of CA3 cells. These findings suggest that the actions of corticotropin-releasing hormone on neuronal excitability in the imm ature hippocampus may play a role in human developmental epilepsies. ( C) 1998 IBRO. Published by Elsevier Science Ltd.