Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H₁ and H₂ receptors, Na⁺‐permeable cation channels, and inward rectifier K⁺ channels

Abstract

In the brain, histamine (HA) serves as a neuromodulator and a neurotransmitter released from the tuberomammillary nucleus (TMN). HA is involved in wakefulness, thermoregulation, energy homeostasis, nociception and learning and memory. The medial entorhinal cortex (MEC) receives inputs from the TMN and expresses HA receptors (H1, H2, and H3). We investigated the effects of HA on GABAergic transmission in the MEC and found that HA significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) with an EC50 of 1.3 μM, but failed to significantly alter sIPSC amplitude. HA-induced increases in sIPSC frequency were sensitive to tetrodotoxin (TTX), required extracellular Ca2+, and persisted when GDP-β-S, a G-protein inactivator, was applied postsynaptically via the recording pipettes, indicating that HA increased GABA release by facilitating the excitability of GABAergic interneurons in the MEC. Recordings from local MEC interneurons revealed that HA significantly increased their excitability as determined by membrane depolarization, generation of an inward current at −65 mV, and augmentation of action potential firing frequency. Both H1 and H2 receptors were involved in HA-induced increases in sIPSCs and interneuron excitability. Immunohistochemical staining showed that both H1 and H2 receptors are expressed on GABAergic interneurons in the MEC. HA-induced depolarization of interneurons involved a mixed ionic mechanism including activation of a Na+-permeable cation channel and inhibition of a cesium-sensitive inward rectifier K+ channel, although HA also inhibited the delayed rectifier K+ channels. Our results may provide a cellular mechanism, at least partially, to explain the roles of HA in the brain.

Impaired Cortical Cytoarchitecture and Reduced Excitability of Deep-Layer Neurons in the Offspring of Diabetic Rats

“…The increase in action potential frequency promoted by histamine in deep-layer cortical neurons is in accordance with the increased excitability previously reported for neurons in other regions of the CNS, namely thalamus (McCormick and Williamson, 1991), layer 6b of the primary somatosensory cortex (Wenger Combremont et al, 2016), entorhinal cortex (Cilz and Lei, 2017), ventral pallidum (Ji et al, 2018), striatum (Zhuang et al, 2018), and spinal cord (Wu et al, 2019). Furthermore, the lack of difference in H 1 R density supports that the electrophysiological changes observed in the offspring of diabetic rats rely mainly on morphological alterations.…”

“…Histamine increases neuronal excitability in several regions of the CNS such as the thalamus ( McCormick and Williamson, 1991 ), layer 6b of the primary somatosensory cortex ( Wenger Combremont et al, 2016 ), entorhinal cortex ( Cilz and Lei, 2017 ), ventral pallidum ( Ji et al, 2018 ), striatum ( Zhuang et al, 2018 ), and spinal cord ( Wu et al, 2019 ). Therefore, we recorded deep layer neurons from P21 pups by injecting depolarizing current in increasing steps under basal and stimulated (1–100 μM histamine) conditions.…”

“…Histamine acts as neuromodulator and neurotransmitter that, among several other functions, participates in spontaneous locomotion. The cerebral cortex is densely innervated by histaminergic fibers and expresses high levels of H 1 receptors (H 1 Rs) (Inagaki et al, 1988;Inoue et al, 1996;Tagawa et al, 2001), and H 1 R activation results in neuron depolarization (McCormick and Williamson, 1991;Reiner and Kamondi, 1994;Wenger Combremont et al, 2016;Cilz and Lei, 2017;Wu et al, 2019).…”

A protocol for preparation and transfection of rat entorhinal cortex organotypic cultures for electrophysiological whole-cell recordings

“…Slices were fixed in 4% paraformaldehyde for 24 h, after which slices were individually transferred to frosted microscope slides (VWR #12-550-15). Immunostaining was performed using methods adapted from previous work [2] . Immunofluorescent staining for the neuronal marker NeuN (1:200, Milipore, #ABN78) demonstrated that EC layers were well-preserved in slice cultures and that neurons were detected after being in culture for several days ( Fig.…”

“…2 B). We next assessed slice health using electrophysiological methods described in previous work [2] . Under high-magnification, differential interference contrast microscopy (DIC) images revealed numerous healthy principal neurons for patching ( Fig.…”