The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats

Abstract

Whole-cell patch-clamp and extracellular field recordings were obtained from 450-μm-thick brain slices of infant rats (10-13 days postnatal) to determine the actions of corticotropin-releasing hormone on glutamate-and GABA-mediated synaptic transmission in the hippocampus. Synthetic corticotropin-releasing hormone (0.15 μM) reversibly increased the excitability of hippocampal pyramidal cells, as determined by the increase in the amplitude of the CA1 population spikes evoked by stimulation of the Schaffer collateral pathway. This increase in population spike amplitude could be prevented by the corticotropin-releasing hormone receptor antagonist α-helical (9-41)-corticotropin-releasing hormone (10 μM). Whole-cell patch-clamp recordings revealed that, in the presence of blockers of fast excitatory and inhibitory synaptic transmission, corticotropin-releasing hormone caused only a small (1-2 mV) depolarization of the resting membrane potential in CA3 pyramidal cells, and it did not significantly alter the input resistance. However, corticotropin-releasing hormone, in addition to decreasing the slow afterhyperpolarization, caused an increase in the number of action potentials per burst evoked by depolarizing current pulses. Corticotropin-releasing 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 currents in CA3 pyramidal cells, without altering their amplitude and single exponential rise and decay time constants. Corticotropin-releasing hormone did not change the amplitude of the pharmacologically isolated (i.e. recorded in the presence of GABA A receptor antagonist bicuculline) excitatory postsynaptic currents in CA3 and CA1 pyramidal cells evoked by stimulation of the mossy fibers and the Schaffer collaterals, respectively. Current-clamp recordings in bicuculline-containing medium showed that, in the presence of corticotropin-releasing hormone, mossy fiber stimulation leads to large, synchronized, polysynaptically-evoked bursts of action potentials in CA3 pyramidal cells. In addition, the peptide caused a small, reversible decrease in the amplitude of the pharmacologically isolated (i.e. recorded in the presence of glutamate receptor antagonists) evoked inhibitory postsynaptic currents in CA3 pyramidal cells, but it did not significantly alter the frequency, amplitude, rise and decay time constants of spontaneous or miniature inhibitory postsynaptic currents.These data demonstrate that corticotropin-releasing hormone, an endogenous neuropeptide whose intracerebroventricular infusion results in seizure activity in immature rats, has diverse effects in the hippocampus which may contribute to epileptogenesis. 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.

Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

“…32 More recently, in vitro studies have shown that CRH modulates glutamatergic mechanisms to increase excitatory neurotransmission in the hippocampal circuit. 6,25 Thus, under physiological circumstances, release of CRH may modulate hippocampal neurotransmission, augmenting glutamate-mediated alterations of hippocampal function. This may influence both normal hippocampal processes such as longterm potentiation and, when excessive, may promote abnormal excitation 1,6,25 and excitotoxicity.…”

“…6,25 Thus, under physiological circumstances, release of CRH may modulate hippocampal neurotransmission, augmenting glutamate-mediated alterations of hippocampal function. This may influence both normal hippocampal processes such as longterm potentiation and, when excessive, may promote abnormal excitation 1,6,25 and excitotoxicity. 9,36,37 The neuroanatomical basis for the influence of CRH on hippocampal neurotransmission has been explored.…”

“…59 Axon terminals of these CRH-immunoreactive interneurons, synapsing on cell bodies of hippocampal principal neurons, are thus strategically positioned to influence neurotransmission in the hippocampal circuit via release of both CRH and GABA. 59 In addition, it has been demonstrated in both the mature and developing hippocampus that application of CRH may lead to excessive excitation of the hippocampal circuit, resulting in repetitive discharges of hippocampal neurons in vitro 1,25,50 and in seizures in vivo. 7,39 It has been suggested that excessive elevation of hippocampal CRH levels may contribute to abnormal neuronal excitation (seizures).…”

“…7,39 It has been suggested that excessive elevation of hippocampal CRH levels may contribute to abnormal neuronal excitation (seizures). 6 Thus, regulation of CRH levels in peptidergic hippocampal neurons may be important for both normal and pathological activation of the hippocampal circuit, 6,25,50 predicting that these levels may be subject to tight physiological control. However, the regulation of CRH expression in the hippocampus has not been elucidated.…”

Hippocampal neuroplasticity induced by early-life stress: Functional and molecular aspects

“…6A and B). When administered icv ('centrally'), CRH reaches the hippocampus [19] where it influences neurons directly [64,20]. Similar to the effects of early-life stress, these CRH-evoked deficits emerged later in adulthood, and were progressive.…”