GABA receptors in the olfactory epithelium of the gilthead seabream (Sparus aurata)

Exposure to high PCO2/low pH seawater induces behavioural alterations in fish; a possible explanation for this is a reversal of Cl−/HCO3− currents through GABAA receptors (the GABAA receptor theory). However, the main evidence for this is that gabazine, a GABAA receptor antagonist, reverses these effects when applied to the water, assuming that exposure to systems other than the CNS would be without effect. Here, we show the expression of both metabotropic and ionotropic GABA receptors, and the presence of GABAA receptor protein, in the olfactory epithelium (OE) of gilthead seabream. Furthermore, exposure of the OE to muscimol (a specific GABAA receptor agonist) increases or decreases the apparent olfactory sensitivity to some odorants. Thus, although the exact function of GABAA receptors in the OE is not yet clear, this may complicate the interpretation of studies wherein water-borne gabazine is used to reverse the effects of high CO2 levels on olfactory-driven behaviour in fish.

Autism-Like Behavior in the Offspring of CYP11A1-Overexpressing Pregnant Rats

Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental disorders that are characterized by impaired social behavior and communication as well as repetitive behavior and restricted interests. Prenatal exposure to high levels of testosterone and preeclampsia are thought to be risk factors of ASD. We had previously reported that overexpression of the mitochondrial cholesterol side-chain cleavage enzyme (CYP11A1) could lead to both preeclampsia-like symptoms and increased testosterone levels in pregnant rats. In this study, we investigated the association between high CYP11A1 levels in pregnant rats and autism-like behavior in their offspring. Timed-pregnant Sprague-Dawley (SD) rats were injected with CYP11A1 gene-carrying adenoviruses on gestational day 8.5, and their offspring were then compared with those from timed-pregnant control SD rats. Compared with their control counterparts, the offspring of the CYP11A1-ovexpressing dams displayed more symptoms of anxiety and spent less time in social interactions and more time in self-grooming and rearing, all indicators of autism-like behavior. Sequencing of the transcriptome in primary microglia from the offspring of CYP11A1-overexpressing dams revealed that immune pathways were highly activated, and the gamma-aminobutyric acid type A (GABAA) receptor genes were among the top differentially expressed genes. Using primary microglia cultures generated from neonatal rats, tumor necrosis factor-alpha expression was found to be elevated in the cells transfected with CYP11A1-carrying adenoviruses. Additionally, the offspring of CYP11A1-overexpressing dams displayed dysregulated GABAA receptor expression. Taken together, these results suggest that abnormal CYP11A1 gene expression in pregnant rats could lead to microglial immune activation and dysregulated GABAA receptor expression in their offspring and thereby anxiety and autism-related behavior. Our study suggests that the pathways regulated by CYP11A1 could be promising preventative and therapeutic targets for ASD.

Activation of the α1β2γ2L GABAA Receptor by Physiological Agonists

The Cl− permeable GABAA receptor is a major contributor to cellular inhibition in the brain. The receptor is normally activated by synaptically-released or ambient GABA but is sensitive to a number of physiological compounds such as β-alanine, taurine, and neurosteroids that, to various degrees, activate the receptor and modulate responses either to the transmitter or to each other. Here, we describe α1β2γ2L GABAA receptor activation and modulation by combinations of orthosteric and allosteric activators. The overall goal was to gain insight into how changes in the levels of endogenous agonists modulate receptor activity and influence cellular inhibition. Experimental observations and simulations are described in the framework of a cyclic concerted transition model. We also provide general analytical solutions for the analysis of electrophysiological data collected in the presence of combinations of active compounds.

The role of neuronal excitation and inhibition in the pre-Bötzinger complex on the cough reflex in the cat

Brainstem respiratory neuronal network significantly contributes to cough motor pattern generation. Neuronal populations in the pre-Bötzinger complex (PreBötC) represent a substantial component for respiratory rhythmogenesis. We studied the role of PreBötC neuronal excitation and inhibition on mechanically induced tracheobronchial cough in 15 spontaneously breathing, pentobarbital anesthetized adult cats (35 mg/kg i.v. initially). Neuronal excitation by unilateral microinjection of glutamate analog D,L-homocysteic acid resulted in mild reduction of cough abdominal electromyogram (EMG) amplitudes and very limited temporal changes of cough compared to effects on breathing (very high respiratory rate, high amplitude inspiratory bursts with a short inspiratory phase and tonic inspiratory motor component). Mean arterial blood pressure temporarily decreased. Blocking glutamate related neuronal excitation by bilateral microinjections of non-specific glutamate receptor antagonist kynurenic acid reduced cough inspiratory and expiratory EMG amplitude and shortened most cough temporal characteristics similarly to breathing temporal characteristics. Respiratory rate decreased and blood pressure temporarily increased. Limiting active neuronal inhibition by unilateral and bilateral microinjections of GABAA receptor antagonist gabazine resulted in lower cough number, reduced expiratory cough efforts, and prolongation of cough temporal features and breathing phases (with lower respiratory rate). The PreBötC is important for cough motor pattern generation. Excitatory glutamatergic neurotransmission in the PreBötC is involved in control of cough intensity and patterning. GABAA receptor related inhibition in the PreBötC strongly affects breathing and coughing phase durations in the same manner, as well as cough expiratory efforts. In conclusion, differences in effects on cough and breathing are consistent with separate control of these behaviors.

β-elemene relieves neuropathic pain in mice through the regulation on C-X-C motif chemokine receptor 3 and GABAA receptor

β-elemene (Bel) is a sesquiterpene compound has shown potential in the antinociceptive treatment. This study focused on the function of Bel in neuropathic pain relief in mice. A murine model with spared nerve injury (SNI) was established and treated with Bel. The paw withdrawal thresholds in response to mechanical and thermal stimulations were examined using von Frey filaments. The L4-L6 spinal dorsal horn tissue samples were collected for histological examination. Bel treatment reduced the sensitivities of model mice to mechanical and thermal stimulations, and it inhibited activation of microglia and the secretion of inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in tissues. Bel treatment reduced the expression of nociceptor excitatory NMDAR whereas enhanced the expression of nociceptor inhibitory GABAA receptor to relieve the nociception of mice. CXCR3 was a downstream molecule mediated by Bel. Either overexpression of CXCR3 or downregulation of GABAA receptor in the tissues aggravated the neuropathic pain in SNI mice which was initially relieved by Bel. In conclusion, this study suggested that Bel might serve as a drug for nociception management by inhibiting CXCR3 and upregulating GABAA receptor. This study may offer novel insights into the field of neuropathic pain relief.

Neurosteroid modulation of GABAA receptor function by independent action at multiple specific binding sites

: Neurosteroids are endogenous modulators of GABAA receptors that mediate anxiety, pain, mood and arousal. The 3-hydroxyl epimers, allopregnanolone (3α-OH) and epi-allopregnanolone (3β-OH) are both prevalent in mammalian brain and produce opposite effects on GABAA receptor function, acting as positive and negative allosteric modulators respectively. This Perspective provides a model to explain the actions of 3α-OH and 3β-OH neurosteroids. The model is based on evidence that the neurosteroid epimers bind to an overlapping subset of specific sites on GABAA receptors, with their net functional effect on channel gating being the sum of their independent effects at each site.

GABAA Receptor-Mediated Sleep-Promoting Effect of Saaz–Saphir Hops Mixture Containing Xanthohumol and Humulone

Hops contain flavonoids that have sedative and sleep-promoting activities such as α-acid, β-acid, and xanthohumol. In this study, the sleep-enhancing activity of a Saaz–Saphir hops mixture was measured. In the caffeine-induced insomnia model, the administration of a Saaz–Saphir mixture increased the sleep time compared to Saaz or Saphir administration alone, which was attributed to the increase in NREM sleep time by the δ-wave increase. Oral administration of the Saaz–Saphir mixture for 3 weeks increased the γ-amino butyric acid (GABA) content in the brain and increased the expression of the GABAA receptor. As the GABA antagonists picrotoxin and bicuculline showed a decrease in sleep activity, it was confirmed that the GABAA receptor was involved in the Saaz–Saphir mixture activity. In addition, the GABAA receptor antagonist also reduced the sleep activity induced by xanthohumol and humulone contained in the Saaz–Saphir mixture. Therefore, xanthohumol and humulone contained in the Saaz–Saphir mixture showed sleep-promoting activity mediated by the GABAA receptors. The mixture of the Saaz and Saphir hop varieties may thus help mitigate sleep disturbances compared to other hop varieties.