Activation of adenosine A2A receptors alters postsynaptic currents and depolarizes neurons of the supraoptic nucleus

2006 ◽  
Vol 291 (2) ◽  
pp. R359-R366 ◽  
Author(s):  
Todd A. Ponzio ◽  
Yu-Feng Wang ◽  
Glenn I. Hatton
Keyword(s):  
Supraoptic Nucleus ◽  
Cell Activity ◽  
Brain Slices ◽  
Cell Types ◽  
Receptor Activation ◽  
A2a Receptors ◽  
Postsynaptic Currents ◽  
Cgs 21680 ◽  
Whole Cell Patch Clamp ◽  
Sites Of Action

Supraoptic nucleus (SON) neurons secrete oxytocin or vasopressin in response to various physiological stimuli (e.g., lactation/suckling, dehydration). Released near fenestrated capillaries of the neurohypophysis, these peptides enter the blood and travel to peripheral target organs. The pervasive neuromodulator adenosine, acting at A1 receptors, is an important inhibitory regulator of magnocellular neuroendocrine cell activity. Another high-affinity adenosine receptor exists in this system, however. We examined the physiological effects of adenosine A2A receptor activation and determined its localization among various cell types within the SON. In whole cell patch-clamp recordings from rat brain slices, application of the selective adenosine A2A receptor agonist CGS-21680 caused membrane depolarizations in SON neurons, often leading to increased firing activity. Membrane potential changes were persistent (>10 min) and could be blocked by the selective A2A receptor antagonist ZM-241385, or GDP-β-S, the latter suggesting postsynaptic sites of action. However, ±-α-methyl-(4-carboxyphenyl)glycine or TTX also blocked CGS-21680 effects, indicating secondary actions on postsynaptic neurons. In voltage-clamp mode, application of CGS-21680 caused a slight increase (∼8%) in high-frequency clusters of excitatory postsynaptic currents. With the use of specific antibodies, adenosine A2A receptors were immunocytochemically localized to both the magnocellular neurons and astrocytes of the SON. Ecto-5′nucleotidase, an enzyme involved in the metabolism of ATP to adenosine, was also localized to astrocytes of the SON. These results demonstrate that adenosine acting at A2A receptors can enhance the excitability of SON neurons and modulate transmitter release from glutamatergic afferents projecting to the nucleus. We suggest that adenosine A2A receptors may function in neuroendocrine regulation through both direct neuronal mechanisms and via actions involving glia.

Dopamine D4 Receptor Activation Inhibits Presynaptically Glutamatergic Neurotransmission in the Rat Supraoptic Nucleus

2001 ◽  
Vol 86 (3) ◽  
pp. 1149-1155 ◽  
Author(s):  
Christopher J. Price ◽  
Quentin J. Pittman
Keyword(s):  
Supraoptic Nucleus ◽  
Sch 23390 ◽  
Receptor Activation ◽  
Glutamatergic Neurotransmission ◽  
Magnocellular Neurons ◽  
Vasopressin Release ◽  
Paired Pulse ◽  
Postsynaptic Currents ◽  
Whole Cell Patch Clamp ◽  
D4 Receptor

Oxytocin and vasopressin release from magnocellular neurons of the supraoptic nucleus is under the control of glutamate-dependent excitation. The supraoptic nucleus also receives a generalized dopaminergic input from hypothalamic sources. To determine if dopamine can influence this excitatory drive onto the magnocellular neurons, we used whole-cell patch clamp to record the effect of dopamine on evoked and miniature excitatory postsynaptic currents in rat hypothalamic slices. Dopamine exposure (30 μM to 1 mM) induced a large and reversible reduction in the amplitude of evoked excitatory postsynaptic current in nearly all magnocellular cells tested. D4 receptors appeared to mediate dopamine's activity, based on inhibition of the response with 50 μM clozapine, but not by SCH 23390 or sulpiride, and mimicry of dopamine's action with the D4 specific agonist, PD 168077. Analysis of paired-pulse experiments and miniature postsynaptic currents indicated that dopamine's action involved a presynaptic mechanism, since the frequency of miniature postsynaptic currents was reduced with dopamine exposure without any change in current kinetics or amplitude, while the paired-pulse ratio increased. We therefore have demonstrated for the first time a role for dopamine D4 receptors in the supraoptic nucleus in the presynaptic inhibition of glutamatergic neurotransmission onto magnocellular neurons.

scholarly journals Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

2020 ◽  
Author(s):  
Stephanie C. Gantz ◽  
Maria M. Ortiz ◽  
Andrew J. Belilos ◽  
Khaled Moussawi
Keyword(s):  
Brain Slices ◽  
Reversal Potential ◽  
Cell Types ◽  
Receptor Activation ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Medium Spiny Neurons ◽  
Inhibitory Function ◽  
Spiny Neurons

SUMMARYUltrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

Histamine Suppresses Non-NMDA Excitatory Synaptic Currents in Rat Supraoptic Nucleus Neurons

2000 ◽  
Vol 83 (5) ◽  
pp. 2616-2625 ◽  
Author(s):  
Zhenhui Li ◽  
Glenn I. Hatton
Keyword(s):  
Supraoptic Nucleus ◽  
Synaptic Currents ◽  
Excitatory Postsynaptic Currents ◽  
Paired Pulse ◽  
Paired Pulse Facilitation ◽  
Postsynaptic Currents ◽  
Whole Cell Patch Clamp ◽  
Bath Application ◽  
Intracellular Diffusion ◽  
Supraoptic Neurons

Whole cell patch-clamp recordings were obtained from supraoptic neurons to investigate the effects of histamine on excitatory postsynaptic currents evoked by electrical stimulation of areas around the posterior supraoptic nucleus. When cells were voltage-clamped at −70 mV, evoked excitatory postsynaptic currents had amplitudes of 88.4 ± 9.6 pA and durations of 41.1 ± 3.0 ms (mean ± SE; n = 43). With twin stimulus pulses (20 Hz) used, paired-pulse facilitation ratios were 1.93 ± 0.12. Bath application of 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX) abolished synaptic currents. Histamine at concentrations ∼0.1–10 μM reversibly suppressed excitatory postsynaptic currents in all supraoptic neurons tested. Within 2 min after application of (10 μM) histamine, current amplitudes and durations decreased by 61.5 and 31.0%, respectively, with little change in the paired-pulse facilitation ratio. Dimaprit or imetit (H2 or H3 receptor agonists) did not reduce synaptic currents, whereas pyrilamine (H1 receptor antagonist) blocked histamine-induced suppression of synaptic currents. When patch electrodes containing guanosine 5′- O-(2-thiodiphosphate) (GDP-β-S) were used to record cells, histamine still suppressed current amplitudes by 49.1% and durations by 41.9%. Similarly, intracellular diffusion of bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA) and H7 did not abolish histamine-induced suppression of synaptic currents, either. Bath perifusion of 8-bromo-quanosine 3′,5′-cyclic monophosphate reduced current amplitudes by 32.3% and durations by 27.9%. After bath perfusion of slices with Nω-nitro-l-arginine methyl ester (L-NAME), histamine injection decreased current amplitudes only by 31.9%, much less than the inhibition rate in control ( P < 0.01). In addition, histamine induced little change in current durations and paired-pulse facilitation ratios, representing a partial blockade of histamine effects on synaptic currents by L-NAME. In supraoptic neurons recorded using electrodes containing BAPTA and perifused with L-NAME, the effects of histamine on synaptic currents were completely abolished. Norepinephrine injection reversibly decreased current amplitudes by 39.1% and duration by 64.5%, with a drop in the paired-pulse facilitation ratio of 47.9%. Bath perifusion of L-NAME, as well as intracellular diffusion of GDP-β-S, , 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine , or BAPTA, failed to block norepinephrine-induced suppression of evoked synaptic currents. The present results suggest that histamine suppresses non- N-methyl-d-aspartate synaptic currents in supraoptic neurons through activation of H1receptors. It is possible that histamine first acts at supraoptic cells (perhaps both neuronal and nonneuronal) and induces the production of nitric oxide, which then diffuses to nearby neurons and modulates synaptic transmission by a postsynaptic mechanism.

Adenosine A2A receptors mediate GABAergic inhibition of respiration in immature rats

2006 ◽  
Vol 100 (1) ◽  
pp. 91-97 ◽  
Author(s):  
Catherine A. Mayer ◽  
Musa A. Haxhiu ◽  
Richard J. Martin ◽  
Christopher G. Wilson
Keyword(s):  
Receptor Activation ◽  
Inhibitory Effect ◽  
Respiratory Drive ◽  
Adult Rats ◽  
A2a Receptors ◽  
Cgs 21680 ◽  
Old Rats ◽  
Apnea Of Prematurity ◽  
Adenosine A2a ◽  
The Relationship

Adenosine is a known inhibitor of respiratory output during early life. In this study we investigated the developmental changes in adenosine A2A-receptor activation on respiratory timing, as well as the relationship between adenosine and GABA. The specific adenosine A2A-receptor agonist CGS-21680 (CGS) or vehicle control was injected into the fourth ventricle of 14-day ( n = 9), 21-day ( n = 9), and adult ( n = 5) urethane-anesthetized rats while diaphragm electromyogram was monitored as an index of respiratory neural output. CGS injection resulted in a decrease in frequency and/or apnea in all 14-day-old rats and in 66% of 21-day-old rats. There was no effect of CGS injection on respiratory timing in adult rats. Prior injection of the GABAA-receptor blocker bicuculline at 14 and 21 days eliminated the CGS-induced decrease in frequency and apnea. We conclude from these studies that the inhibitory effect of A2A-receptor activation on respiratory drive is age dependent and is mediated via GABAergic inputs to the inspiratory timing neural circuitry. These findings demonstrate an important mechanism by which xanthine therapy alleviates apnea of prematurity.

scholarly journals Role of Connexin 36 in Autoregulation of Oxytocin Neuronal Activity in Rat Supraoptic Nucleus

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141984376 ◽  
Author(s):  
Ping Wang ◽  
Stephani C. Wang ◽  
Dongyang Li ◽  
Tong Li ◽  
Hai-Peng Yang ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Supraoptic Nucleus ◽  
Brain Slices ◽  
Virgin Female ◽  
Female Rats ◽  
Dye Coupling ◽  
Connexin 36 ◽  
Postsynaptic Currents ◽  
Junctional Communication ◽  
Vasopressin Neurons

In the supraoptic nucleus (SON), the incidence of dye coupling among oxytocin (OT) neurons increases significantly in nursing mothers. However, the type(s) of connexin (Cx) involved is(are) unknown. In this study, we specifically investigated whether Cx36 plays a functional role in the coupling between OT neurons in the SON of lactating rats. In this brain region, Cx36 was mainly coimmunostained with vasopressin neurons in virgin female rats, whereas in lactating rats, Cx36 was primarily colocalized with OT neurons. In brain slices from lactating rats, application of quinine (0.1 mM), a selective blocker of Cx36, significantly reduced dye coupling among OT neurons as well as the discharge/firing frequency of spikes/action potentials and their amplitude, and transiently depolarized the membrane potential of OT neurons in whole-cell patch-clamp recordings. However, quinine significantly reduced the amplitude, but not frequency, of inhibitory postsynaptic currents in OT neurons; the duration of excitatory postsynaptic currents was reduced but not their frequency and amplitude. Furthermore, the excitatory effect of OT (1 pM) on OT neurons was significantly weakened and delayed by quinine, and burst firing was absent in the presence of this inhibitor. Lastly, Western blotting analysis revealed that the presence of combined, but not alone, quinine and OT significantly reduced the amount of Cx36 in the SON. Thus, Cx36-mediated junctional communication plays a crucial role in autoregulatory control of OT neuronal activity, likely by acting at the postsynaptic sites. The level of Cx36 is modulated by its own activity and the presence of OT.

scholarly journals Opioid-Mediated Astrocyte–Neuron Signaling in the Nucleus Accumbens

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 586 ◽  
Author(s):  
Michelle Corkrum ◽  
Patrick E. Rothwell ◽  
Mark J. Thomas ◽  
Paulo Kofuji ◽  
Alfonso Araque
Keyword(s):  
Nucleus Accumbens ◽  
Opioid Receptor ◽  
Molecular Mechanisms ◽  
Brain Slices ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Μ Opioid Receptor ◽  
Patch Clamp Electrophysiology

Major hallmarks of astrocyte physiology are the elevation of intracellular calcium in response to neurotransmitters and the release of neuroactive substances (gliotransmitters) that modulate neuronal activity. While μ-opioid receptor expression has been identified in astrocytes of the nucleus accumbens, the functional consequences on astrocyte–neuron communication remains largely unknown. The present study has investigated the astrocyte responsiveness to μ-opioid signaling and the regulation of gliotransmission in the nucleus accumbens. Through the combination of calcium imaging and whole-cell patch clamp electrophysiology in brain slices, we have found that μ-opioid receptor activation in astrocytes elevates astrocyte cytoplasmic calcium and stimulates the release of the gliotransmitter glutamate, which evokes slow inward currents through the activation of neuronal N-methyl-D-aspartate (NMDA) receptors. These results indicate the existence of molecular mechanisms underlying opioid-mediated astrocyte–neuron signaling in the nucleus accumbens.

scholarly journals Excitation of medium spiny neurons by ‘inhibitory’ ultrapotent chemogenetics via shifts in chloride reversal potential

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Stephanie C Gantz ◽  
Maria M Ortiz ◽  
Andrew J Belilos ◽  
Khaled Moussawi
Keyword(s):  
Brain Slices ◽  
Reversal Potential ◽  
Cell Types ◽  
Receptor Activation ◽  
D1 Receptor ◽  
Medium Spiny Neurons ◽  
Inhibitory Function ◽  
Spiny Neurons

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs and in vitro as indicated by cell-attached recordings from D1-MSNs in mouse brain slices. Whole-cell recordings showed that activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. These data show that ‘inhibitory’ PSAM4-GlyR chemogenetics may activate certain cell types and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

scholarly journals Contribution of Ionotropic Glutamatergic Receptors to Excitability and Attentional Signals in Macaque Frontal Eye Field

2021 ◽  
Author(s):  
Miguel Dasilva ◽  
Christian Brandt ◽  
Marc Alwin Gieselmann ◽  
Claudia Distler ◽  
Alexander Thiele
Keyword(s):  
Attentional Control ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Cell Types ◽  
Receptor Activation ◽  
Frontal Eye Field ◽  
Control Signals ◽  
Cognitive Operations ◽  
Eye Field ◽  
Large Scale Networks

Abstract Top-down attention, controlled by frontal cortical areas, is a key component of cognitive operations. How different neurotransmitters and neuromodulators flexibly change the cellular and network interactions with attention demands remains poorly understood. While acetylcholine and dopamine are critically involved, glutamatergic receptors have been proposed to play important roles. To understand their contribution to attentional signals, we investigated how ionotropic glutamatergic receptors in the frontal eye field (FEF) of male macaques contribute to neuronal excitability and attentional control signals in different cell types. Broad-spiking and narrow-spiking cells both required N-methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation for normal excitability, thereby affecting ongoing or stimulus-driven activity. However, attentional control signals were not dependent on either glutamatergic receptor type in broad- or narrow-spiking cells. A further subdivision of cell types into different functional types using cluster-analysis based on spike waveforms and spiking characteristics did not change the conclusions. This can be explained by a model where local blockade of specific ionotropic receptors is compensated by cell embedding in large-scale networks. It sets the glutamatergic system apart from the cholinergic system in FEF and demonstrates that a reduction in excitability is not sufficient to induce a reduction in attentional control signals.

scholarly journals Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function

2021 ◽  
Vol 22 (2) ◽  
pp. 666
Author(s):  
Toshio Takahashi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Embryonic Stem ◽  
Cholinergic Neurons ◽  
Cell Types ◽  
Proliferative Potential ◽  
True Nature ◽  
Cholinergic Signaling

Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of damage and extend organismal life beyond that of component cells, and they probably preceded the evolution of complex metazoans. Understanding the true nature of stem cells can only come from discovering how they are regulated. The concept that stem cells are controlled by particular microenvironments, also known as niches, has been widely accepted. Technical advances now allow characterization of the zones that maintain and control stem cell activity in several organs, including the brain, skin, and gut. Cholinergic neurons release acetylcholine (ACh) that mediates chemical transmission via ACh receptors such as nicotinic and muscarinic receptors. Although the cholinergic system is composed of organized nerve cells, the system is also involved in mammalian non-neuronal cells, including stem cells, embryonic stem cells, epithelial cells, and endothelial cells. Thus, cholinergic signaling plays a pivotal role in controlling their behaviors. Studies regarding this signal are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and they are expected to advance efforts to control stem cells therapeutically. The present article reviews recent findings about cholinergic signaling that is essential to control stem cell function in a cholinergic niche.

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