scholarly journals Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

2021 ◽  
Author(s):  
Ryan David Shepard ◽  
Kunwei Wu ◽  
Wei Lu
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Excitability ◽  
Critical Role ◽  
Cell Voltage ◽  
General Anesthetics ◽  
Physiological Basis ◽  
Lateral Habenula ◽  
Sleep Physiology ◽  
Presynaptic Release ◽  
Synaptic Drive

Sleep is a fundamental physiological process conserved across most species. As such, deficits in sleep can result in a myriad of psychological and physical health issues. However, the mechanisms underlying the induction of sleep are relatively unknown. Interestingly, general anesthetics cause unconsciousness by positively modulating GABA-A receptors (GABAARs). Based on this observation, it is hypothesized that GABAARs play a critical role in modulating circuits involved in sleep to promote unconsciousness. Recently, the lateral habenula (LHb) has been demonstrated to play a role in sleep physiology and sedation. Specifically, propofol has been shown to excite LHb neurons to promote sedation. However, the mechanism by which this occurs is unknown. Here, we utilize whole-cell voltage and current clamp recordings from LHb neurons obtained from 8-10 week old male mice to determine the physiological mechanisms for this phenomenon. We show that bath application of 1.5μM propofol is sufficient to increase LHb neuronal excitability involving synaptic transmission, but not through modulation of intrinsic properties. Additionally, although there is increased LHb neuronal excitability, GABAARs localized postsynaptically on LHb neurons are still responsive to propofol, as indicated by an increase in the decay time. Lastly, we find that propofol increases the synaptic drive onto LHb neurons involving enhanced presynaptic release of both glutamate and GABA. However, the greatest contributor to the potentiated synaptic drive is the increased release of glutamate which shifts the balance of synaptic transmission towards greater excitation. Taken together, this study is the first to identify the physiological basis for why LHb neurons are excited by propofol, rather than inhibited, and as a result promote sedation.

Sevoflurane Induced Suppression of Inhibitory Synaptic Transmission Between Soma-Soma Paired Lymnaea Neurons

1999 ◽  
Vol 82 (5) ◽  
pp. 2812-2819 ◽  
Author(s):  
Toshiro Hamakawa ◽  
Zhong-Ping Feng ◽  
Nikita Grigoriv ◽  
Takuya Inoue ◽  
Mayumi Takasaki ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Cell Voltage ◽  
Synaptic Depression ◽  
Membrane Properties ◽  
Inhibitory Synapses ◽  
General Anesthetics ◽  
Inhibitory Synaptic Transmission ◽  
Transmitter Receptors ◽  
Lymnaea Neurons

The cellular and synaptic mechanisms by which general anesthetics affect cell-cell communications in the nervous system remain poorly defined. In this study, we sought to determine how clinically relevant concentrations of sevoflurane affected inhibitory synaptic transmission between identified Lymnaea neurons in vitro. Inhibitory synapses were reconstructed in cell culture, between the somata of two functionally well-characterized neurons, right pedal dorsal 1 (RPeD1, the giant dopaminergic neuron) and visceral dorsal 4 (VD4). Clinically relevant concentrations of sevoflurane (1–4%) were tested for their effects on synaptic transmission and the intrinsic membrane properties of soma-soma paired cells. RPeD1- induced inhibitory postsynaptic potentials (IPSPs) in VD4 were completely and reversibly blocked by sevoflurane (4%). Sevoflurane also suppressed action potentials in both RPeD1 and VD4 cells. To determine whether the anesthetic-induced synaptic depression involved postsynaptic transmitter receptors, dopamine was pressure applied to VD4, either in the presence or absence of sevoflurane. Dopamine (10−]5 M) activated a voltage-insensitive K+ current in VD4. The same K+ current was also altered by sevoflurane; however, the effects of two compounds were nonadditive. Because transmitter release from RPeD1 requires Ca2+ influx through voltage-gated Ca2+ channels, we next tested whether the anesthetic-induced synaptic depression involved these channels. Individually isolated RPeD1 somata were whole cell voltage clamped, and Ca2+ currents were analyzed in control and various anesthetic conditions. Clinically relevant concentrations of sevoflurane did not significantly affect voltage-activated Ca2+ channels in RPeD1. Taken together, this study provides the first direct evidence that sevoflurane-induced synaptic depression involves both pre- and postsynaptic ion channels.

scholarly journals Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula

2020 ◽  
Author(s):  
Sarah C. Simmons ◽  
Ryan D. Shepard ◽  
Shawn Gouty ◽  
Ludovic D. Langlois ◽  
Brian M. Cox ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
P38 Mapk ◽  
Life Stress ◽  
Early Life ◽  
Neuronal Excitability ◽  
Early Life Stress ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Lateral Habenula ◽  
Reward Circuitry

AbstractThe lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb intrinsic excitability while blunting the response of LHb neurons to extra hypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn-KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerts differential effects on the excitability of two distinct subpopulations of LHb neurons that differ in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increases neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreases neuronal excitability in small/negative Ih (Ih-) neurons. Additionally, we found that an intact fast-synaptic transmission is required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission. While stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons, we found that U50, 488 either increased or decreased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreased mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. While total p38 MAPK (a downstream signaling pathway driven by KOR activation) expression was elevated in the LHb of MD rats compared to non-MD controls, we found that application of KOR-specific agonist, U50,488, onto LHb slices was still able to alter phosphorylated p38 MAPK (ph-p38) expression in MD rats similar to non-MD controls. Moreover, we found that the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of the functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

scholarly journals PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jingliang Zhang ◽  
Chenyu Zhang ◽  
Xiaoling Chen ◽  
Bingwei Wang ◽  
Weining Ma ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Granule Cells ◽  
Critical Role ◽  
Intrinsic Excitability ◽  
Seizure Susceptibility ◽  
Seizure Onset ◽  
Potential Therapeutic Target ◽  
Seizure Model

AbstractTemporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.

Y5 Receptors Mediate Neuropeptide Y Actions at Excitatory Synapses in Area CA3 of the Mouse Hippocampus

2002 ◽  
Vol 87 (1) ◽  
pp. 558-566 ◽  
Author(s):  
Hui Guo ◽  
Peter A. Castro ◽  
Richard D. Palmiter ◽  
Scott C. Baraban
Keyword(s):  
Synaptic Transmission ◽  
Neuropeptide Y ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Receptor Subtype ◽  
Limbic Seizures ◽  
Excitatory Transmission ◽  
Npy Receptor ◽  
Bath Application ◽  
Peptide Agonist

Neuropeptide Y (NPY) is a potent modulator of excitatory synaptic transmission and limbic seizures. NPY is abundantly expressed in the dentate gyrus and is thought to modulate hippocampal excitability via activation of presynaptic Y2 receptors (Y2R). Here we demonstrate that NPY, and commonly used Y2R-preferring (NPY13–36) and Y5 receptor (Y5R)–preferring ([d-Trp32]NPY and hPP) peptide agonists, evoke similar levels of inhibition at excitatory CA3 synapses in hippocampal slices from wild-type control mice (WT). In contrast, NPYergic inhibition of excitatory CA3 synaptic transmission is absent in mice lacking the Y5R subtype (Y5R KO). In both analyses of evoked population spike activity and spontaneous excitatory postsynaptic synaptic currents (EPSCs), NPY agonists induced powerful inhibitory effects in all hippocampal slices from WT mice, whereas these peptides had no effect in slices from Y5R KO mice. In slices from WT mice, NPY (and NPY receptor–preferring agonists) reduced the frequency of spontaneous EPSCs but had no effect on sEPSC amplitude, rise time, or decay time. Furthermore, NPYergic modulation of spontaneous EPSCs in WT mice was mimicked by bath application of a novel Y5R-selective peptide agonist ([cpp]hPP) but not the selective Y2R agonist ([ahx5–24]NPY). In situ hybridization was used to confirm the presence of NPY, Y2, and Y5 mRNA in the hippocampus of WT mice and the absence of Y5R in knockout mice. These results suggest that the Y5 receptor subtype, previously believed to mediate food intake, plays a critical role in modulation of hippocampal excitatory transmission at the hilar-to-CA3 synapse in the mouse.

Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

2004 ◽  
Vol 92 (3) ◽  
pp. 1658-1667 ◽  
Author(s):  
Mark C. Bieda ◽  
M. Bruce MacIver
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Intrinsic Excitability ◽  
High Potassium ◽  
Ca1 Neurons ◽  
Adult Rat ◽  
Adult Rat Brain ◽  
Sites Of Action

Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABAA inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABAA but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABAA-mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABAA-mediated inhibition using the GABAA receptor antagonist SR95531 (gabazine). Gabazine (20 μM) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABAA inhibition. Glutamatergic synaptic responses were not altered by propofol (≤30 μM). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABAA conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABAA conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

Postsynaptic mechanisms underlying long-term depression of GABAergic transmission in neurons of the deep cerebellar nuclei

1996 ◽  
Vol 76 (1) ◽  
pp. 59-68 ◽  
Author(s):  
W. Morishita ◽  
B. R. Sastry
Keyword(s):  
Synaptic Transmission ◽  
Gabaa Receptor ◽  
Cell Voltage ◽  
Cerebellar Nuclei ◽  
Neuronal Membrane ◽  
Gamma Aminobutyric Acid ◽  
Deep Cerebellar Nuclei ◽  
Long Term Depression ◽  
In Cells

1. The mechanisms underlying long-term depression (LTD) of gamma-aminobutyric acid-A (GABAA) receptor-mediated synaptic transmission induced by 10-Hz stimulation of the inhibitory afferents were investigated using perforated and whole cell voltage-clamp recordings from neurons of the deep cerebellar nuclei (DCN). 2. LTD of inhibitory postsynaptic currents (IPSCs) was reliably induced when the 10-Hz stimulation was delivered under current-clamp conditions where the postsynaptic neuronal membrane was allowed to depolarize. 3. Currents elicited by local applications of the GABAA receptor agonist, 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3-ol hydrochloride (THIP) were also depressed during LTD. 4. LTD could be induced heterosynaptically and did not require the activation of GABAA receptors during the 10-Hz stimulation. 5. In cells loaded with QX-314 and superfused with media containing 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonovaleric acid (APV), a series of depolarizing pulses (50 mV, 200 ms) induced a sustained depression of the IPSC. However, this was not observed in cells recorded with high bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA)-containing pipette solutions or when they were exposed to the L-type Ca2+ channel antagonist, nitrendipine. 6. The 10-Hz-induced LTD was also inhibited by BAPTA and was significantly reduced when DCN cells were loaded with microcystin LR or treated with okadaic acid, both inhibitors of protein phosphatases. 7. These results indicate that increases in postsynaptic [Ca2+] and phosphatase activity can reduce the efficacy of GABAA receptor-mediated synaptic transmission.

Melatonin receptor activation increases glutamatergic synaptic transmission in the rat medial lateral habenula

Synapse ◽  
2016 ◽  
Vol 70 (5) ◽  
pp. 181-186 ◽  
Author(s):  
Katherine M. Evely ◽  
Randall L. Hudson ◽  
Margarita L. Dubocovich ◽  
Samir Haj-dahmane
Keyword(s):  
Synaptic Transmission ◽  
Receptor Activation ◽  
Melatonin Receptor ◽  
Lateral Habenula ◽  
Glutamatergic Synaptic Transmission

scholarly journals Identification of a putative binding site critical for general anesthetic activation of TRPA1

2017 ◽  
Vol 114 (14) ◽  
pp. 3762-3767 ◽  
Author(s):  
Hoai T. Ton ◽  
Thieu X. Phan ◽  
Ara M. Abramyan ◽  
Lei Shi ◽  
Gerard P. Ahern
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Halogen Bond ◽  
Critical Role ◽  
Sensory Nerves ◽  
Structural Basis ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Potential Binding

General anesthetics suppress CNS activity by modulating the function of membrane ion channels, in particular, by enhancing activity of GABAA receptors. In contrast, several volatile (isoflurane, desflurane) and i.v. (propofol) general anesthetics excite peripheral sensory nerves to cause pain and irritation upon administration. These noxious anesthetics activate transient receptor potential ankyrin repeat 1 (TRPA1), a major nociceptive ion channel, but the underlying mechanisms and site of action are unknown. Here we exploit the observation that pungent anesthetics activate mammalian but not Drosophila TRPA1. Analysis of chimeric Drosophila and mouse TRPA1 channels reveal a critical role for the fifth transmembrane domain (S5) in sensing anesthetics. Interestingly, we show that anesthetics share with the antagonist A-967079 a potential binding pocket lined by residues in the S5, S6, and the first pore helix; isoflurane competitively disrupts A-967079 antagonism, and introducing these mammalian TRPA1 residues into dTRPA1 recapitulates anesthetic agonism. Furthermore, molecular modeling predicts that isoflurane and propofol bind to this pocket by forming H-bond and halogen-bond interactions with Ser-876, Met-915, and Met-956. Mutagenizing Met-915 or Met-956 selectively abolishes activation by isoflurane and propofol without affecting actions of A-967079 or the agonist, menthol. Thus, our combined experimental and computational results reveal the potential binding mode of noxious general anesthetics at TRPA1. These data may provide a structural basis for designing drugs to counter the noxious and vasorelaxant properties of general anesthetics and may prove useful in understanding effects of anesthetics on related ion channels.

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