Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels

Abstract

Corticotropin-releasing hormone (CRH) plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSP) were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean ± Standard error of the mean; 231.8 ± 31.2% of control; n = 10) while neither affecting fEPSPs (104.3 ± 4.2%; n = 10) nor long-term potentiation (LTP). However, when Schaffer-collaterals were excited via action potentials (APs) generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n = 8) and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1) expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca2+-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity.

Hyper-diversity of CRH interneurons in mouse hippocampus

“…Thus, it is tempting to speculate that CRH co-expression may be associated with different firing patterns of these PV-containing interneuron classes, either through different expression profile of specific voltage-gated ion channels (e.g., K + channels) or via the peptide modulating intrinsic neuronal excitability in an autocrine manner. In pyramidal cells, CRH activation of CRHR1 results in an increase in neuronal excitability at least in part through the inhibition of Ca 2+ -dependent K + channel function (Aldenhoff et al 1983;, as well as through the attenuation of fast A-type and delayed rectifier K-type K + currents (Kratzer et al 2013). Given that such an increase in the excitability of CRH interneurons is not apparent here, and to date, CRH receptors have only been identified on pyramidal cells, it would seem more likely that CRH coexpression may be associated with changes in the expression of ion channels that underlie intrinsic neuronal properties.…”

“…The principal receptor for this peptide, CRH receptor 1 (CRHR1), resides at specific subcellular locations on pyramidal cells (Chen et al 2000), while CRH receptor 2 (CRHR2) is restricted to the axon initial segment of these neurons (Joels and Baram 2009). Electrophysiological studies have demonstrated that within the hippocampus both exogenous and endogenously released CRH, primarily increases pyramidal cell excitability via multiple mechanisms including the inhibition of Ca 2+ -dependent K + channel function (Aldenhoff et al 1983;Haug and Storm 2000; and attenuating A-type K + channel activation (Kratzer et al 2013). CRH is rapidly released within the hippocampus following stress and this peptide has been implicated in mediating some of the stress-induced effects upon hippocampal function (Chen et al 2004(Chen et al , 2010.…”

Stress and Seizures: Space, Time and Hippocampal Circuits

“…Application of CRH results in a rapid dose-dependent increase in the excitability of CA1 and CA3 pyramidal cells [50–52], most likely through a reduction in the I AHP that occurs following action potentials [50, 53] and, at least in CA1, the inhibition of A-type K + channel function [54]. Consistent with these effects of exogenous peptide, endogenous CRH increased action potential firing and excitatory transmission onto CA3 pyramidal cells in the acute hippocampal slice.…”

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

“…Such changes may be mediated by the HPA axis or through the immune system. Treatment of mouse hippocampal slices with corticotropin-releasing hormone seems to alter neuronal excitability depending on L- and T-type calcium channels and also on voltage-gated potassium channels [147]. Antidepressants can alter neuronal excitability by altering calcium and potassium channels, acting as an environmental trigger for mood episodes [148,149].…”