Delia Belelli - Academia.edu (original) (raw)

Papers by Delia Belelli

British Journal of Pharmacology, Jun 1, 1996

British Journal of Pharmacology, Feb 20, 2013

Frontiers in Neuroscience, 2011

British Journal of Pharmacology, Aug 1, 2002

Journal of Neuroendocrinology, 2021

Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to b... more Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be “fine‐tuned” by these neurosteroids to influence behaviour. In preclinical studies, these neurosteroids exhibited anxiolytic, anticonvulsant, analgesic and sedative properties and, at relatively high doses, induced a state of general anaesthesia, a profile consistent with their interaction with GABAARs. However, realising the therapeutic potential of either endogenous neurosteroids or synthetic “neuroactive” steroids has proven challenging. Recent approval by the Food and Drug Administration of the use of allopregnanolone (brexanolone) to treat postpartum depression has rekindled enthusiasm for exploring their potential as new medicines. Althoug...

Neurobiology of Stress, 2019

The Journal of Neuroscience, 2003

The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous gene... more The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABAAreceptors, with selectivity for β2 and β3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive β2 subunit (β2 N265S) to determine the role of β2 and β3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through β3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the β2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABAAreceptor subtypes.

Neuropharmacology, 2017

In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibiti... more In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the "benzodiazepine site". However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on (3)H-flumazenil binding, but displaced the GABAAR agonist (3)H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse h...

Journal of neuroendocrinology, Jan 14, 2017

GABA plays a key role in both embryonic and neonatal brain development. For example, during early... more GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABAA receptors (GABAA Rs), undergoes a temporally specific form of synaptic plasticity, to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABAA Rs, is reduced, permitting neurons to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABAA R are primarily implicated in this plasticity. However, it is now evident that in developing thalamic and cortical principal- and inter-neurons an endogenous neurosteroid tone e.g. allopregnanolone, enhances synaptic GABAA R function. Furthermore, a cessation of steroidogenesis, due to a lack of substrate, or a co-factor, appears primarily respons...

Genes, brain, and behavior, Jan 19, 2016

GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian br... more GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarise the evidence that variations in genes encoding GABAA receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABAA receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarise the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABAA Receptor Subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour.

Neuropharmacology, Jan 25, 2015

As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program o... more As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signaling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 30, 2014

The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tr... more The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tract (GIT) and regulates virtually all GI functions. Altered neuronal activity within the ENS underlies various GI disorders with stress being a key contributing factor. Thus, elucidating the expression and function of the neurotransmitter systems, which determine neuronal excitability within the ENS, such as the GABA-GABAA receptor (GABAAR) system, could reveal novel therapeutic targets for such GI disorders. Molecular and functionally diverse GABAARs modulate rapid GABAergic-mediated regulation of neuronal excitability throughout the nervous system. However, the cellular and subcellular GABAAR subunit expression patterns within neurochemically defined cellular circuits of the mouse ENS, together with the functional contribution of GABAAR subtypes to GI contractility remains to be determined. Immunohistochemical analyses revealed that immunoreactivity for the GABAAR gamma (γ) 2 and alpha...

Frontiers in Neuroendocrinology, 2015

Brain Structure and Function, 2014

The Journal of Physiology, 2011

Non‐Technical Summary To be effective, synaptic transmission requires precise alignment of the p... more Non‐Technical Summary To be effective, synaptic transmission requires precise alignment of the presynaptic terminal, releasing the neurotransmitter, with the postsynaptic density, where receptors are present at high density. Complex molecular mechanisms ensure this interplay between neurons and, in addition, stabilize receptors in the postsynaptic membrane. To explore these mechanisms at GABAergic synapses, which mediate inhibitory neurotransmission in the brain, we investigated here the consequences of ‘removing’ the receptors, using targeted gene deletion. Our results show that the receptors are dispensable for synapse formation, but are required for the postsynaptic aggregation of several proteins involved in receptor trafficking, anchoring and regulation. Defects in the molecular regulation of GABAergic synapses have been associated with neurodevelopmental disorders, mental retardation, anxiety and mood disorders, underscoring the relevance of fine tuning of GABAergic inhibitio...

The Journal of Physiology, 2008

Thalamic ventrobasal (VB) relay neurones express multiple GABAA receptor subtypes mediating phasi... more Thalamic ventrobasal (VB) relay neurones express multiple GABAA receptor subtypes mediating phasic and tonic inhibition. During postnatal development, marked changes in subunit expression occur, presumably reflecting changes in functional properties of neuronal networks. The aims of this study were to characterize the properties of synaptic and extrasynaptic GABAA receptors of developing VB neurones and investigate the role of the α1 subunit during maturation of GABA‐ergic transmission, using electrophysiology and immunohistochemistry in wild type (WT) and α10/0 mice and mice engineered to express diazepam‐insensitive receptors (α1H101R, α2H101R). In immature brain, rapid (P8/9–P10/11) developmental change to mIPSC kinetics and increased expression of extrasynaptic receptors (P8–27) formed by the α4 and δ subunit occurred independently of the α1 subunit. Subsequently (≥ P15), synaptic α2 subunit/gephyrin clusters of WT VB neurones were replaced by those containing the α1 subunit. Su...

The Journal of Neuroscience, 2009

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAAand GABABreceptors... more GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAAand GABABreceptors. Recently, a novel form of GABAAreceptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAAreceptors underlie classical “phasic” GABAAreceptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAAreceptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAAreceptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This mini-symposium review highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAAreceptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAArecept...

The Journal of Neuroscience, 2014

Within the nucleus accumbens (NAc), synaptic GABAAreceptors (GABAARs) mediate phasic inhibition o... more Within the nucleus accumbens (NAc), synaptic GABAAreceptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/−or α4−/−mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/−mice did not differ in their expression of cocaine-conditioned place p...

The Journal of Neuroscience, 2013

Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and... more Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and generate pathological activities during absence epilepsy. Inhibitory control of thalamocortical (TC) relay neurons is partially mediated by GABA released from neurons of the thalamic reticular nucleus (nRT), acting predominantly via synaptic α1β2γ2 GABAAreceptors (GABAARs). Importantly, TC neurons also express extrasynaptic α4β2δ GABAARs, although how they cooperate with synaptic GABAARs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABAAR-lacking, α4 “knock-out” (α40/0) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in α40/0pairs, suggesting that action ...