Mu-opioid Receptors Facilitate the Propagation of Excitatory Activity in Rat Hippocampal Area CA1 by Disinhibition of all Anatomical Layers

2003 ◽  
Vol 90 (3) ◽  
pp. 1936-1948 ◽  
Author(s):  
A. Rory McQuiston ◽  
Peter Saggau
Keyword(s):  
Opioid Receptors ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Gaba Release ◽  
Inhibitory Interneuron ◽  
Perforant Path ◽  
Stratum Radiatum ◽  
Receptor Antagonists ◽  
Area Ca1 ◽  
Excitatory Activity

Hippocampal μ-opioid receptors (MORs) have been implicated in memory formation associated with opiate drug abuse. MORs modulate hippocampal synaptic plasticity acutely, when chronically activated, and during drug withdrawal. At the network level, MORs increase excitability in area CA1 by disinhibiting pyramidal cells. The precise inhibitory interneuron subtypes affected by MOR activation are unknown; however, not all subtypes are inhibited, and specific interneuron subtypes have been shown to preferentially express MORs. Here we investigate, using voltage-sensitive dye imaging in brain slices, the effect of MOR activation on the patterns of inhibition and on the propagation of excitatory activity in rat hippocampal CA1. MOR activation augments excitatory activity evoked by stimulating inputs in stratum oriens [i.e., Schaffer collateral and commissural pathway (SCC) and antidromic], stratum radiatum (i.e., SCC), and stratum lacunosum-moleculare (SLM; i.e., perforant path and thalamus). The augmented excitatory activity is further facilitated as it propagates through the CA1 network. This was observed as a proportionately larger increase in amplitudes of excitatory activity at sites distal from where the activity was evoked. This facilitation was observed for excitatory activity propagating from all three stimulation sites. The augmentation and facilitation were prevented by GABAA receptor antagonists (bicuculline, 30 μM), but not by GABAB receptor antagonists (CGP 55845, 10 μM). Furthermore, MOR activation inhibited IPSPs in all layers of area CA1. These findings suggest that MOR-induced suppression of GABA release onto GABAA receptors augments all inputs to CA1 pyramidal cells and facilitates the propagation of excitatory activity through the network of area CA1.

scholarly journals Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms

2019 ◽  
Author(s):  
Priyodarshan Goswamee ◽  
A. Rory McQuiston
Keyword(s):  
Receptor Antagonist ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Inhibitory Interneuron ◽  
Stratum Radiatum ◽  
Synaptic Efficacy ◽  
Ach Release ◽  
Paired Pulse ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Ca1

AbstractIn hippocampal CA1, muscarinic acetylcholine (ACh) receptor (mAChR) activation via exogenous application of cholinergic agonists has been shown to presynaptically inhibit Schaffer collateral (SC) glutamatergic inputs in stratum radiatum (SR), and temporoammonic (TA) and thalamic nucleus reuniens (RE) glutamatergic inputs in stratum lacunosum-moleculare (SLM). However, steady-state uniform mAChR activation may not mimic the effect of ACh release in an intact hippocampal network. To more accurately examine the effect of ACh release on glutamatergic synaptic efficacy, we measured electrically evoked synaptic responses in CA1 pyramidal cells (PCs) following the optogenetic release of ACh in genetically modified mouse brain slices. The ratio of synaptic amplitudes in response to paired-pulse SR stimulation (stimulus 2/stimulus 1) was significantly reduced by the optogenetic release of ACh, consistent with a postsynaptic decrease in synaptic efficacy. The effect of ACh release was blocked by the M3 receptor antagonist 4-DAMP, the GABAB receptor antagonist CGP 52432, inclusion of GDP-β-S, cesium, QX314 in the intracellular patch clamp solution, or extracellular barium. These observations suggest that ACh release decreased SC synaptic transmission through an M3 muscarinic receptor-mediated increase in inhibitory interneuron excitability, which activate GABAB receptors and inwardly rectifying potassium channels on CA1 pyramidal cells. In contrast, the ratio of synaptic amplitudes in response to paired-pulse stimulation in the SLM was increased by ACh release, consistent with presynaptic inhibition. ACh-mediated effects in SLM were blocked by the M2 receptor antagonist AF-DX 116, presumably located on presynaptic terminals. Therefore, our data indicate that ACh release differentially modulates excitatory inputs in SR and SLM of CA1 through different cellular and network mechanisms.

Hippocampal Interneurons Are Excited Via Serotonin-Gated Ion Channels

1997 ◽  
Vol 78 (5) ◽  
pp. 2493-2502 ◽  
Author(s):  
Lori L. McMahon ◽  
Julie A. Kauer
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Negative Slope ◽  
Patch Clamp Recording ◽  
Gated Ion Channels

McMahon, Lori L. and Julie A. Kauer. Hippocampal interneurons are excited via serotonin-gated ion channels. J. Neurophysiol. 78: 2493–2502, 1997. Serotonergic neurons of the median raphe nucleus heavily innervate hippocampal GABAergic interneurons located in stratum radiatum of area CA1, suggesting that this strong subcortical projection may modulate interneuron excitability. Using whole cell patch-clamp recording from interneurons in brain slices, we tested the effects of serotonin (5-HT) on the physiological properties of these interneurons. Serotonin produces a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic glutamate and γ-aminobutyric acid (GABA) receptor antagonists. The 5-HT–induced current was independent of G-protein activation. Pharmacological evidence indicates that 5-HT directly excites these interneurons through activation of 5-HT3 receptors. At membrane potentials negative to −55 mV, the current-voltage ( I-V) relationship of the 5-HT current displays a region of negative slope conductance. Therefore the response of interneurons to 5-HT strongly depends on membrane potential and increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT–induced currents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT–responsive interneurons ramify widely within CA1; some of these interneurons also project to and arborize extensively in the dentate gyrus. The organization of these inhibitory connections strongly suggests that these cells regulate excitability of both CA1 pyramidal cells and dentate granule cells. As our results indicate that 5-HT may mediate fast excitatory synaptic transmission onto these interneurons, serotonergic inputs can simultaneously modulate the output of both hippocampus and dentate gyrus.

Entorhinal inputs to hippocampal CA1 and dentate gyrus in the rat: a current-source-density study

1995 ◽  
Vol 73 (6) ◽  
pp. 2392-2403 ◽  
Author(s):  
L. S. Leung ◽  
L. Roth ◽  
K. J. Canning
Keyword(s):  
Dentate Gyrus ◽  
Cell Body ◽  
Granule Cells ◽  
Current Source ◽  
Pyramidal Cells ◽  
Short Latency ◽  
Current Source Density ◽  
Perforant Path ◽  
Stratum Radiatum ◽  
Source Density

1. Laminar profiles of the average evoked potentials and current-source-density analysis were used to study the input provided by the medial perforant path (PP) to the hippocampus in the urethan-anesthetized rat. 2. Stimulation of the PP activated an early latency sink in the middle molecular layer of the dentate gyrus (DG) and in the stratum lacunosum-moleculare in CA1. The DG current sink was generated by excitatory synaptic currents activated by the PP on dentate granule cells. In the normal rat, the peak current sink in the DG was typically five times greater than that of CA1. However, the CA1 sink could be distinguished from the DG sink in several ways: 1) it peaked when the DG sink was subsiding; 2) it showed paired-pulse facilitation, whereas the DG sink did not; and 3) in rats in which the DG was lesioned by local colchicine injection, the DG sink was reduced much more than the CA1 sink. 3. The PP afferents to CA1 required a slightly higher stimulus threshold (> 100 microA) for activation than those projecting to the DG granule cells (< 30 microA). The onset latency of the early CA1 sink (2.5 +/- 0.2 ms, mean +/- SE) was also slightly longer than that of the DG sink (1.7 +/- 0.1 ms), suggesting that the axons of entorhinal layer III cells that project to CA1 have a slightly lower conduction velocity than the axons of the layer II cells that project to the DG. 4. The short-latency current sink activated by the PP in the distal dendritic layers of CA1 was likely provided by excitatory currents at the distal apical dendrites of CA1 pyramidal cells. The accompanying current source was mainly confined to stratum radiatum and appeared not to involve the cell body layer. Thus the electrotonic current spread may not be effective enough to depolarize the cell body or axon hillock. Contribution of interneurons to the above source-sink profile is possible, with the provision that these interneurons must have dendritic processes that span strata radiatum and lacunosum moleculare. 5. Extracellular field recordings provided no evidence that PP evoked a short-latency (< 9 ms) CA1-generated population spike, even with the use of micropipettes filled with mM bicuculline. Similarly, unit recordings in CA1 revealed only long-latency (9-17 ms) unit firing after PP stimulation, corresponding to a late, di/trisynaptic excitation of CA1 via the Schaffer collaterals.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Photopotentiation of the GABAA receptor with caged diazepam

2019 ◽  
Vol 116 (42) ◽  
pp. 21176-21184 ◽  
Author(s):  
Lorenzo Sansalone ◽  
Joshua Bratsch-Prince ◽  
Sicheng Tang ◽  
Burjor Captain ◽  
David D. Mott ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Basolateral Amygdala ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Gaba Release ◽  
Intrinsic Activity ◽  
Gabaergic Synapses ◽  
The Central Nervous System ◽  
Complementary Nature ◽  
Inhibitory Signaling

As the inhibitory γ-aminobutyric acid–ergic (GABAergic) transmission has a pivotal role in the central nervous system (CNS) and defective forms of its synapses are associated with serious neurological disorders, numerous versions of caged GABA and, more recently, photoswitchable ligands have been developed to investigate such transmission. While the complementary nature of these probes is evident, the mechanisms by which the GABA receptors can be photocontrolled have not been fully exploited. In fact, the ultimate need for specificity is critical for the proper synaptic exploration. No caged allosteric modulators of the GABAA receptor have been reported so far; to introduce such an investigational approach, we exploited the structural motifs of the benzodiazepinic scaffold to develop a photocaged version of diazepam (CD) that was tested on basolateral amygdala (BLa) pyramidal cells in mouse brain slices. CD is devoid of any intrinsic activity toward the GABAA receptor before irradiation. Importantly, CD is a photoreleasable GABAA receptor-positive allosteric modulator that offers a different probing mechanism compared to caged GABA and photoswitchable ligands. CD potentiates the inhibitory signaling by prolonging the decay time of postsynaptic GABAergic currents upon photoactivation. Additionally, no effect on presynaptic GABA release was recorded. We developed a photochemical technology to individually study the GABAA receptor, which specifically expands the toolbox available to study GABAergic synapses.

Interneurons in Area CA1 Stratum Radiatum and Stratum Oriens Remain Functionally Connected to Excitatory Synaptic Input in Chronically Epileptic Animals

1997 ◽  
Vol 78 (3) ◽  
pp. 1504-1515 ◽  
Author(s):  
D. A. Rempe ◽  
E. H. Bertram ◽  
J. M. Williamson ◽  
E. W. Lothman
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Synaptic Input ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Ca1 Pyramidal Cells ◽  
Control Tissue ◽  
Stratum Oriens ◽  
Area Ca1 ◽  
Excitatory Synaptic Input

Rempe, D. A., E. H. Bertram, J. M. Williamson, and E. W. Lothman. Interneurons in area CA1 stratum radiatum and stratum oriens remain functionally connected to excitatory synaptic input in chronically epileptic animals. J. Neurophysiol. 78: 1504–1515, 1997. Past work has demonstrated a reduction of stimulus-evoked inhibitory input to hippocampal CA1 pyramidal cells in chronic models of temporal lobe epilepsy (TLE). It has been postulated that this reduction in inhibition results from impaired excitation of inhibitory interneurons. In this report, we evaluate the connectivity of area CA1 interneurons to their excitatory afferents in hippocampal-parahippocampal slices obtained from a rat model of chronic TLE. Rats were made chronically epileptic by a period of continuous electrical stimulation of the hippocampus, which establishes an acute condition of self-sustained limbic status epilepticus (SSLSE). This period of SSLSE is followed by a development of chronic recurrent spontaneous limbic seizures that are associated with chronic neuropathological changes reminiscent of those encountered in human TLE. Under visual control, whole cell patch-clamp recordings of interneurons and pyramidal cells were obtained in area CA1 of slices taken from adult, chronically epileptic post-SSLSE rats. Neurons were activated by means of electrodes positioned in stratum radiatum. Intrinsic membrane properties, including resting membrane potential, action potential (AP) threshold, AP half-height width, and membrane impedance, were unchanged in interneurons from chronically epileptic (post-SSLSE) tissue compared with control tissue. Single stimuli delivered to stratum radiatum evoked depolarizing excitatory postsynaptic potentials and APs in interneurons, whereas paired-pulse stimulation evoked facilitation of the postsynaptic current (PSC) in both control and post-SSLSE tissue. No differences between interneurons in control versus post-SSLSE tissue could be found with respect to the mean stimulus intensity or mean stimulus duration needed to evoke an AP. A multiple linear regression analysis over a range of stimulus intensities demonstrated that a greater number of APs could be evoked in interneurons in post-SSLSE tissue compared with control tissue. Spontaneous PSCs were observed in area CA1 interneurons in both control and post-SSLSE tissue and were markedly attenuated by glutamatergic antagonists. In conclusion, our data suggest that stimulus-evoked and spontaneous excitatory synaptic input to area CA1 interneurons remains functional in an animal model of chronic temporal lobe epilepsy. These findings suggest, therefore, that the apparent decrease of polysynaptic inhibitory PSPs in CA1 pyramidal cells in epileptic tissue is not due to a deficit in excitatory transmission from Schaffer collaterals to interneurons in stratum radiatum and straum oriens.

GAT-3 Transporters Regulate Inhibition in the Neocortex

2005 ◽  
Vol 94 (6) ◽  
pp. 4533-4537 ◽  
Author(s):  
Gregory A. Kinney
Keyword(s):  
Pyramidal Cells ◽  
Gaba Release ◽  
Inhibitory Interneuron ◽  
Inhibitory Interneurons ◽  
Slice Preparation ◽  
Rat Neocortex ◽  
Ambient Gaba ◽  
Layer V

The role of GAT-3 transporters in regulating GABAA receptor-mediated inhibition was examined in the rat neocortex using an in vitro slice preparation. Pharmacologically isolated GABAA receptor-mediated responses were recorded from layer V neocortical pyramidal cells, and the effects of SNAP-5114, a GAT-3 GABA transporter-selective antagonist, were evaluated. Application of SNAP-5114 resulted in a reversible increase in the amplitude of an evoked GABAA response in most cells examined, although no effect on the decay time was observed. Examination of the spontaneous output of inhibitory interneurons revealed a reversible increase in the frequency and amplitude of spontaneous inhibitory synaptic currents as a consequence of GAT-3 inhibition. This effect of GAT-3 inhibition on spontaneous inhibitory events was action potential-dependent because no such increases were observed when SNAP-5114 was applied in the presence of TTX. These results demonstrate that GAT-3 transporters regulate inhibitory interneuron output in the neocortex. The increase in inhibitory interneuron excitability resulting from application of SNAP-5114 suggests that inhibition of GAT-3 transporter function results in a reduction in ambient GABA levels, possibly by a reduction in carrier-mediated GABA release via the GAT-3 transporter.

Activation of δ-Opioid Receptors Excites Spinally Projecting Locus Coeruleus Neurons Through Inhibition of GABAergic Inputs

2002 ◽  
Vol 88 (5) ◽  
pp. 2675-2683 ◽  
Author(s):  
Yu-Zhen Pan ◽  
De-Pei Li ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Locus Coeruleus ◽  
Dorsal Horn ◽  
Opioid Receptors ◽  
Brain Slices ◽  
Gaba Release ◽  
Current Clamp ◽  
Excitatory Effect ◽  
Inhibitory System ◽  
Postsynaptic Currents

Stimulation of the noradrenergic nucleus locus coeruleus (LC) releases norepinephrine in the spinal cord, which inhibits dorsal horn neurons and produces analgesia. Activation of this descending noradrenergic pathway also contributes to the analgesic action produced by systemic opioids. The δ-opioid receptors are present presynaptically in the LC. However, their functional role in the control of the activity of spinally projecting LC neurons remains uncertain. In this study, we tested the hypothesis that activation of presynaptic δ-opioid receptors excites spinally projecting LC neurons through inhibition of GABA release. Spinally projecting LC neurons were retrogradely labeled by a fluorescent dye, DiI, injected into the spinal dorsal horn of rats. Whole cell voltage- and current-clamp recordings were performed on DiI-labeled LC neurons in brain slices in vitro. Retrogradely labeled LC noradrenergic neurons were demonstrated by dopamine-β-hydroxylase immunofluorescence. [d-Pen2,d-Pen5]-enkephalin (DPDPE, 1 μM) significantly decreased the frequency of GABA-mediated miniature inhibitory postsynaptic currents (IPSCs) of nine DiI-labeled LC neurons from 2.1 ± 0.5 to 0.7 ± 0.2 Hz without altering their amplitude and the kinetics. On the other hand, the miniature excitatory postsynaptic currents (EPSC) of nine DiI-labeled LC neurons were not significantly altered by DPDPE. Furthermore, DPDPE significantly inhibited the amplitude of evoked IPSC but not EPSC in eight DiI-labeled LC neurons. Under the current-clamp condition, the firing activity in 9 of 11 DiI-labeled LC neurons was significantly increased by 1 μM DPDPE from 4.6 ± 0.7 to 6.2 ± 1.0 Hz. Bicuculline (20 μM) also significantly increased the firing frequency in 13 of 20 neurons from 1.8 ± 0.5 to 2.8 ± 0.6 Hz. Additionally, the excitatory effect of DPDPE on LC neurons was diminished in the presence of bicuculline. Collectively, these data strongly suggest that activation of presynaptic δ-opioid receptors by DPDPE excites a population of spinally projecting LC neurons by preferential inhibition of GABA release. Thus presynaptic δ-opioid receptors likely play an important role in the regulation of the excitability of spinally projecting LC neurons and the descending noradrenergic inhibitory system.

Mu opioid receptors inhibit GABA release from parvalbumin interneuron terminals onto CA1 pyramidal cells

2020 ◽  
Vol 522 (4) ◽  
pp. 1059-1062
Author(s):  
Caifeng Shao ◽  
Pei Chen ◽  
Qian Chen ◽  
Mingwei Zhao ◽  
Wei-Ning Zhang ◽  
...  
Keyword(s):  
Opioid Receptors ◽  
Pyramidal Cells ◽  
Gaba Release ◽  
Mu Opioid Receptors ◽  
Mu Opioid ◽  
Ca1 Pyramidal Cells ◽  
Parvalbumin Interneuron

Effects of μ-Opioid Receptor Modulation on GABAB Receptor Synaptic Function in Hippocampal CA1

2007 ◽  
Vol 97 (3) ◽  
pp. 2301-2311 ◽  
Author(s):  
A. Rory McQuiston
Keyword(s):  
Gabab Receptor ◽  
Gaba Release ◽  
Excitatory Input ◽  
Synaptic Function ◽  
Stratum Radiatum ◽  
Stratum Pyramidale ◽  
Receptor Modulation ◽  
Excitatory Activity ◽  
Hippocampal Ca1 ◽  
Cgp 55845

Activation of μ-opioid receptors (MORs) alters information coding, synaptic plasticity, and spatial memory in hippocampal CA1. In CA1, MORs act by inhibiting GABA release onto both GABAA and GABAB receptors exclusively. MOR activation can facilitate excitatory inputs in CA1 dendritic layers by inhibiting synaptic activation of GABAA receptors. In this study, we use voltage-sensitive dye imaging to show that MOR activation by the MOR agonist DAMGO suppressed GABAB inhibitory postsynaptic potentials in all layers of CA1. When stimulating excitatory input in stratum oriens (SO), stratum radiatum (SR), or stratum lacunosum-moleculare (SLM) with five pulses at 20 Hz in the presence of bicuculline (50 μM), DAMGO (1 μM) was most effective at increasing the amplitude of the last excitatory event. This effect was reversed by the MOR antagonist CTOP (1 μM) and occluded by the GABAB receptor agonist CGP 55845 (10 μM). DAMGO was less effective at increasing the amplitude of later excitatory events compared with the effect of CGP 55845. DAMGO was relatively ineffective at increasing the amplitude of excitatory inputs in SLM but had significantly greater effects on excitatory events as they propagated to stratum pyramidale (SP). When stimulating in SR, DAMGO was least effective at increasing excitatory amplitudes in SLM and most effective in SP and SO. Finally, DAMGO was equally effective at increasing excitatory activity amplitudes in all layers of CA1 after stimulating in SO. Therefore MOR suppresses GABAB synaptic hyperpolarizations in all layers of CA1 and most effectively facilitates excitatory activity in CA1 output layers.

scholarly journals Downregulation of Astrocytic Kir4.1 Potassium Channels Is Associated with Hippocampal Neuronal Hyperexcitability in Type 2 Diabetic Mice

2020 ◽  
Vol 10 (2) ◽  
pp. 72 ◽  
Author(s):  
Miguel P. Méndez-González ◽  
David E. Rivera-Aponte ◽  
Jan Benedikt ◽  
Geronimo Maldonado-Martínez ◽  
Flavia Tejeda-Bayron ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Diabetic Mice ◽  
Patch Clamp Recording ◽  
Neuronal Hyperexcitability ◽  
Ca1 Pyramidal Neurons ◽  
Type 2 Diabetic

Epilepsy, characterized by recurrent seizures, affects 1% of the general population. Interestingly, 25% of diabetics develop seizures with a yet unknown mechanism. Hyperglycemia downregulates inwardly rectifying potassium channel 4.1 (Kir4.1) in cultured astrocytes. Therefore, the present study aims to determine if downregulation of functional astrocytic Kir4.1 channels occurs in brains of type 2 diabetic mice and could influence hippocampal neuronal hyperexcitability. Using whole-cell patch clamp recording in hippocampal brain slices from male mice, we determined the electrophysiological properties of stratum radiatum astrocytes and CA1 pyramidal neurons. In diabetic mice, astrocytic Kir4.1 channels were functionally downregulated as evidenced by multiple characteristics including depolarized membrane potential, reduced barium-sensitive Kir currents and impaired potassium uptake capabilities of hippocampal astrocytes. Furthermore, CA1 pyramidal neurons from diabetic mice displayed increased spontaneous activity: action potential frequency was ≈9 times higher in diabetic compared with non-diabetic mice and small EPSC event frequency was significantly higher in CA1 pyramidal cells of diabetics compared to non-diabetics. These differences were apparent in control conditions and largely pronounced in response to the pro-convulsant 4-aminopyridine. Our data suggest that astrocytic dysfunction due to downregulation of Kir4.1 channels may increase seizure susceptibility by impairing astrocytic ability to maintain proper extracellular homeostasis.

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