Sergiy Sylantyev

The vast majority of ionotropic glycine receptor research has historically concentrated on receptor function in neurons and, to a somewhat lesser extent, in myocytes. However, an ever-increasing volume of experimental data indicates the important role of glycine receptor in cytoprotective and modulatory effects in nonexcitable cells and tissues. The key mechanisms underlying these glycine receptor effects are connected to the regulation of the electrical potential of the plasmalemma, Ca ²⁺ influx from the extracellular media, and Ca ²⁺ efflux from the endoplasmic reticulum. These mechanisms trigger a complex network of biochemical signaling pathways that, in turn, partially regulate glycine receptor activity. In addition, glycine effects in several cell types suggest the existence of modulatory signaling chains of a yet unknown nature. Taken together, these findings clearly demonstrate the important role of the glycine receptor in understudied (although widespread) molecular and cellular mechanisms of potentially high significance. Therefore, we provide a brief review of glycine receptor effects on different types of nonexcitable cells, and we believe that targeting glycine receptor in nonexcitable cells is a potential strategy for regenerative medicine in the clinic.

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. The brainstem nucleus of the solitary tract (NTS) receives direct information from the digestive system and projects to second order regions in the brain. Though γ-Aminobutyric acid is widely expressed in the NTS (GABA ^NTS ), its function has not been defined. Characterization of GABA cells using single nucleus RNA sequencing (Nuc-Seq) identified at least 19 clusters. Here we provide insight into the function of GABA ^NTS cells, revealing that selective activation of GABA ^NTS neurons significantly controls food intake and body weight. Optogenetic interrogation of GABA ^NTS circuitry identified GABA ^NTS →arcuate nucleus of the hypothalamus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed GABA ^NTS →ARC stimulation inhibits hunger promoting agouti-related protein/neuropeptide Y (AgRP/NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABA ^NTS →ARC circuit induces satiety. These data identify GABA ^NTS as a new modulator of feeding behavior, body weight and controller of orexigenic AgRP/NPY activity, thereby providing insight into the neural underpinnings of obesity. Highlights: Nucleus of the solitary tract (NTS) GABA neurons are responsive to nutritional status. Chemogenetic GABA ^NTS neuron activation reduces food intake and body weight. GABA ^NTS projections to the hypothalamic arcuate nucleus (ARC) promote satiety. Optogenetic GABA ^NTS →ARC stimulation inhibits orexigenic AgRP/NPY neurons. In Brief: Martinez de Morentin et al. identify GABAergic neurons in the nucleus of the solitary tract as a new player in the circuit governing feeding behavior and body weight.

Brain ischemic stroke is among the leading causes of death and long-term disability. New treatments that alleviate brain cell damage until blood supply is restored are urgently required. The emerging focus of anti-stroke strategies has been on blood-brain-barrier permeable drugs that exhibit multiple sites of action. Here, we combine single-cell electrophysiology with live-cell imaging to find that β-Alanine (β-Ala) protects key physiological functions of brain cells that are exposed to acute stroke-mimicking conditions in ex vivo brain preparations. β-Ala exerts its neuroprotective action through several distinct pharmacological mechanisms, none of which alone could reproduce the neuroprotective effect. Since β-Ala crosses the blood-brain barrier and is part of a normal human diet, we suggest that it has a strong potential for acute stroke treatment and facilitation of recovery.

Neutrophils are white blood cells that are critical to the acute inflammatory and adaptive immune responses. While their diverse interactions with tissue cells and pathogens have been intensely studied, little is known about how they communicate among themselves. Here we employ up-to-date neuroscience techniques to find that electrical, mechanical, or ligand stimulation of an individual neutrophil triggers Ca²⁺ mobilisation in nearby cells by engaging their NMDA receptors. Glutamate imaging reveals that the activated cells in turn release glutamate thus triggering a chain reaction that generates long-range signal exchange among the neutrophil assembly. These observations uncover a regenerative-wave mechanism - NMDA receptor dependent glutamate-induced glutamate release - that enables remote communication, or a signal-spreading ‘detonation’ - among blood cells.

Global warming and connected acidification of the world ocean attract a substantial amount of research efforts, in particular in a context of their impact on behaviour and metabolism of marine organisms, such as Cnidaria. Nevertheless, mechanisms underlying Cnidarians’ neural signalling and behaviour and their (possible) alterations due to the world ocean acidification remain poorly understood. Here we researched for the first time modulation of GABA_A receptors (GABA_ARs) in Actinia equina (Cnidaria: Anthozoa) by pH fluctuations within a range predicted by the world ocean acidification scenarios for the next 80–100 years and by selective pharmacological activation. We found that in line with earlier studies on vertebrates, both changes of pH and activation of GABA_ARs with a selective allosteric agonist (diazepam) modulate electrical charge transfer through GABA_AR and the whole-cell excitability. On top of that, diazepam modifies the animal behavioural reaction on startle response. However, despite behavioural reactions displayed by living animals are controlled by GABA_ARs, changes of pH do not alter them significantly. Possible mechanisms underlying the species resistance to acidification impact are discussed.

Human embryonic stem cell (hESC)‐derived midbrain dopamine (DA) neurons stand out as a cell source for transplantation with their sustainability and consistency superior to the formerly used fetal tissues. However, multiple studies of DA neurons in culture failed to register action potential (AP) generation upon synaptic input. To test whether this is due to deficiency of NMDA receptor (NMDAR) coagonists released from astroglia, we studied the functional properties of neural receptors in hESC‐derived DA neuronal cultures. We find that, apart from an insufficient amount of coagonists, lack of interneuronal crosstalk is caused by hypofunction of synaptic NMDARs due to their direct inhibition by synaptically released DA. This inhibitory tone is independent of DA receptors and affects the NMDAR coagonist binding site.

Key points: Rapid changes in neuronal network activity trigger widespread waves of extracellular GABA in hippocampal neuropil. Elevations of extracellular GABA narrow the coincidence detection window for excitatory inputs to CA1 pyramidal cells. GABA transporters control the effect of extracellular GABA on coincidence detection. Small changes in the kinetics of dendritic excitatory currents amplify when reaching the soma. Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feedforward inhibitory circuit also involving the hyperpolarisation‐activated I_h current. However, afferent connections often bypass feedforward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA 'sniffer' patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly widens the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade shortens it. The underlying mechanism involves membrane‐shunting tonic GABA_A receptor current; it does not have to rely on I_h but depends strongly on the neuronal GABA transporter GAT‐1. We use dendrite‐soma dual patch‐clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.