Histamine H3 Heteroreceptors Suppress Glutamatergic and GABAergic Synaptic Transmission in the Rat Insular Cortex

Abstract

Histamine H3 receptors are autoreceptors that regulate histamine release from histaminergic neuronal terminals. The cerebral cortex, including the insular cortex (IC), expresses abundant H3 receptors; however, the functions and mechanisms of H3 receptors remain unknown. The aim of this study was to elucidate the functional roles of H3 in synaptic transmission in layer V of the rat IC. Unitary excitatory and inhibitory postsynaptic currents (uEPSCs and uIPSCs) were obtained through paired whole-cell patch-clamp recording in cerebrocortical slice preparations. The H3 receptor agonist, R-α-methylhistamine (RAMH), reduced the uEPSC amplitude obtained from pyramidal cell to pyramidal cell or GABAergic interneuron connections. Similarly, RAMH reduced the uIPSC amplitude in GABAergic interneuron to pyramidal cell connections. RAMH-induced decreases in both the uEPSC and uIPSC amplitudes were accompanied by increases in the failure rate and paired-pulse ratio. JNJ 5207852 dihydrochloride or thioperamide, H3 receptor antagonists, inhibited RAMH-induced suppression of uEPSCs and uIPSCs. Unexpectedly, thioperamide alone increased the uIPSC amplitude, suggesting that thioperamide was likely to act as an inverse agonist. Miniature EPSC or IPSC recordings support the hypothesis that the activation of H3 receptors suppresses the release of glutamate and GABA from presynaptic terminals. The colocalization of H3 receptors and glutamate decarboxylase or vesicular glutamate transport protein 1 in presynaptic axon terminals was confirmed through double pre-embedding microscopy, using a combination of pre-embedding immunogold and immunoperoxidase techniques. The suppressive regulation of H3 heteroreceptors on synaptic transmission might mediate the regulation of sensory information processes, such as gustation and visceral sensation, in the IC.

Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice

“…In a recent study, conditional genetic restoration of Mecp2 expression in GABAergic neurons rescued multiple disease features in a mouse model of RTT [35], which supports the critical regulatory role of GABAergic inhibitory neurons in phenotypes of RTT. GABA is a principal inhibitory neurotransmitter, and GABAergic neurons comprise a functionally confirmed diverse cell population in the mammalian central nervous system [36,37,38,39,40]. It is currently unknown how MeCP2 supports GABA synthesis and how the deletion of Mecp2 affects pre- and post-synaptic GABAergic inhibitory functions in the brain [14,31,35,37,41,42].…”

Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats

“…induces generalized myoclonic and/or tonic-clonic seizures) [ 11 , 53 , 54 , 55 ]. The failure of RAMH to reverse the protections provided by H3R antagonist 4 might be explained with its capability to reduce the suppression of glutamatergic and GABAergic synaptic transmission through blockade of H3 heteroreceptor function in CNS, necessitating additional future investigations of whether H3R antagonist 4 modulated the release of inhibitory neurotransmitters, for example, GABA [ 56 ].…”

“…Notably, STR is an established competitive antagonist of the inhibitory amino acid glycine. Therefore, the inability of H3R antagonist 13 to afford a dose-dependent protection against STR-induced seizure model advocates little or no modulation effect of H3R antagonist 13 on the glycine receptors, because the mechanisms underlying STR-induced seizures are supposed to be attributed to its blocking activity on glycine receptors in the brain as well as in the spinal cord [ 56 ]. Notably, most marketed AEDs were not effective in all conducted convulsion models during preclinical drug development.…”

Trigeminal Nerve Transection-Induced Neuroplastic Changes in the Somatosensory and Insular Cortices in a Rat Ectopic Pain Model

“…The VGAT-Venus line A transgenic rats ( N = 31) were used for the in vitro whole-cell patch-clamp recording. The techniques used to prepare the in vitro cortical slices were similar to those previously described (Takei et al, 2017; Yamamoto and Kobayashi, 2018). Briefly, the rats were anesthetized with isoflurane (5%) and decapitated.…”