Presynaptic glycine receptors facilitate spontaneous glutamate release onto hilar neurons in the rat hippocampus

Abstract

Although glycine receptors are found in most areas of the brain, including the hippocampus, their functional significance remains largely unknown. In the present study, we have investigated the role of presynaptic glycine receptors on excitatory nerve terminals in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs) were recorded in mechanically dissociated rat dentate hilar neurons attached with native presynaptic nerve terminals using a conventional whole‐cell patch recording technique under voltage‐clamp conditions. Exogenously applied glycine or taurine significantly increased the frequency of sEPSCs in a concentration‐dependent manner. This facilitatory effect of glycine was blocked by 1 μM strychnine, a specific glycine receptor antagonist, but was not affected by 30 μM picrotoxin. In addition, Zn2+ (10 μM) potentiated the glycine action on sEPSC frequency. Pharmacological data suggested that the activation of presynaptic glycine receptors directly depolarizes glutamatergic terminals resulting in the facilitation of spontaneous glutamate release. Bumetanide (10 μM), a specific Na‐K‐2C co‐transporter blocker, gradually attenuated the glycine‐induced sEPSC facilitation, suggesting that the depolarizing action of presynaptic glycine receptors was due to a higher intraterminal Cl− concentration. The present results suggest that presynaptic glycine receptors on excitatory nerve terminals might play an important role in the excitability of the dentate gyrus‐hilus‐CA3 network in physiological and/or pathological conditions.

Presynaptic Glycine Receptors Influence Plasma Membrane Potential and Glutamate Release

“…The aim of our paper is to fill the gap between reports clearly indicating involving of glycine transporters to glutamate release [16][17][18][19] and reports from electrophysiological labs suggesting involving of chloride-driven membrane depolarization [8][9][10]12].…”

“…The activation of presynaptic glycine receptors in neurons leads to a decrease of potential difference followed by neurotransmitter release [8][9][10]. This release is sensitive to strychnine, a glycine receptor inhibitor [8,10].…”

Changes in neural network homeostasis trigger neuropsychiatric symptoms

“…Targeted presynaptic GlyR HA-α3L 185L protein expression in vivo was confirmed using the HA epitope tag at the receptor N terminus (24,27,28) in immunohistochemical and ultrastructural analyses. Presynaptic GlyR expression is known to facilitate synaptic transmission due to a depolarized chloride reversal potential for axonal versus perisomatic ligand-gated chloride channels (49)(50)(51)(52)(53), and consistently, presynaptic GlyR HA-α3L 185L influenced the paired-pulse ratio of postsynaptic currents and decreased the amplitude of evoked excitatory field potentials when expressed in glutamatergic or parvalbumin-positive neurons, respectively. This presynaptic mode of GlyR α3L 185L action in vivo persistently enhanced neuronal function, affected neural network excitability in a neuron type-specific way, and triggered neuropsychiatric symptoms reminiscent of the epilepsy psychopathology, all of which identify an antihomeostatic role for changes in presynaptic function.…”

Microinjection of Glycine into the Hypothalamic Paraventricular Nucleus Produces Diuresis, Natriuresis, and Inhibition of Central Sympathetic Outflow

“…For these studies the selective glycine receptor antagonist strychnine (Lee et al, 2009) was microinjected into the PVN (1.6 nmol) 10 min before vehicle or glycine (50 nmol). Changes in cardiovascular and renal excretory function and RSNA were measured during consecutive 10-min periods before (control) and after (experimental) drug injection for 80 min.…”

“…Participation of the renal sympathetic nerves in mediating glycine-induced changes in renal excretory function was examined by directly measuring changes in renal sympathetic nerve activity (RSNA) and repeating the experimental protocol in rats that had undergone chronic bilateral renal denervation. Finally, separate experiments were performed to determine the effects produced by bilateral microinjection of strychnine, a highly selective and potent competitive glycine receptor antagonist (Lee et al, 2009), into the PVN on cardiovascular and renal excretory function and RSNA. For these studies, strychnine was injected into animals alone or as a pretreatment before glycine injection.…”