Pathway-Specific Targeting of GABAA Receptor Subtypes to Somatic and Dendritic Synapses in the Central Amygdala

2001 ◽  
Vol 86 (2) ◽  
pp. 717-723 ◽  
Author(s):  
Andrew J. Delaney ◽  
Pankaj Sah
Keyword(s):  
Gaba Receptors ◽  
Large Amplitude ◽  
Gaba Receptor ◽  
Small Amplitude ◽  
Inhibitory Synapses ◽  
Receptor Subtypes ◽  
Central Amygdala ◽  
Low Concentrations ◽  
Gabaa Receptor Subtypes ◽  
Minimal Stimulation

Neurons in the central amygdala express two distinct types of ionotropic GABA receptor. One is the classical GABAA receptor that is blocked by low concentrations of bicuculline and positively modulated by benzodiazepines. The other is a novel type of ionotropic GABA receptor that is less sensitive to bicuculline but blocked by the GABAC receptor antagonist (1,2,5,6-tetrohydropyridine-4-yl) methylphosphinic acid (TPMPA) and by benzodiazepines. In this study, we examine the distribution of these two receptor types. Recordings of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) showed a wide variation in amplitude. Most events had amplitudes of <50 pA, but a small minority had amplitudes >100 pA. Large-amplitude events also had rise times faster than small-amplitude events. Large-amplitude events were fully blocked by 10 μM bicuculline but unaffected by TPMPA. Small amplitude events were partially blocked by both bicuculline and TPMPA. Focal application of hypertonic sucrose to the soma evoked large-amplitude mIPSCs, whereas focal dendritic application of sucrose evoked small-amplitude mIPSCs. Thus inhibitory synapses on the dendrites of neurons in the central amygdala express both types of GABA receptor, but somatic synapses expressed purely GABAA receptors. Minimal stimulation revealed that inhibitory inputs arising from the laterally located intercalated cells innervate dendritic synapses, whereas inhibitory inputs of medial origin innervated somatic inhibitory synapses. These results show that different types of ionotropic GABA receptors are targeted to spatially and functionally distinct synapses. Thus benzodiazepines will have different modulatory effects on different inhibitory pathways in the central amygdala.

GABAC receptors on ferret retinal bipolar cells: A diversity of subtypes in mammals?

1997 ◽  
Vol 14 (5) ◽  
pp. 989-994 ◽  
Author(s):  
Peter D. Lukasiewicz ◽  
Rachel O.L. Wong
Keyword(s):  
Receptor Antagonist ◽  
Large Amplitude ◽  
Small Amplitude ◽  
Ganglion Cells ◽  
Cell Voltage ◽  
Bipolar Cells ◽  
Receptor Subtypes ◽  
Evoked Responses ◽  
Gabac Receptor ◽  
Gabac Receptors

AbstractThe GABAC receptor subtypes on bipolar cells of rats and cold-blooded vertebrates differ in their pharmacological properties and probably have different molecular compositions. With the exception of the rat, native GABAC receptors in mammals had not been studied. In ferret, whole-cell, voltage-clamp recordings were made from bipolar cells in the retinal slice preparation to determine which subtype of GABAC receptor predominated. Puff-evoked GABA currents in bipolar cells were partially reduced by the GABAA receptor antagonist bicuculline, indicating that both GABAA and GABAC receptors mediated the responses. By contrast, GABA currents of ganglion cells were always completely blocked by bicuculline, indicating that GABAA receptors predominated on these cells. Small-amplitude GABA currents of bipolar cells evoked by short-duration puffs were less sensitive to bicuculline than large-amplitude currents evoked by long-duration puffs. This indicates that GABAc receptors mediated proportionately more of the small-amplitude, puff-evoked responses and GABAA receptors mediated more of the large-amplitude, puff-evoked responses. In bipolar cells, the bicuculline-resistant component of the GABA current was entirely blocked by 3-APMPA (3-aminopropyl-(methyl)phosphonic acid), a GABAC receptor antagonist. Picrotoxin, which is relatively ineffective at rat GABAC receptors, completely blocked GABA currents in ferret bipolar cells, indicating that GABAC receptors on ferret bipolar cells resemble those in lower vertebrates rather than those in the rat retina. These results suggest that there may be a diversity of GABAc receptor subtypes on mammalian bipolar cells.

scholarly journals The Clustering of GABAA Receptor Subtypes at Inhibitory Synapses is Facilitated via the Direct Binding of Receptor  2 Subunits to Gephyrin

2008 ◽  
Vol 28 (6) ◽  
pp. 1356-1365 ◽  
Author(s):  
V. Tretter ◽  
T. C. Jacob ◽  
J. Mukherjee ◽  
J.-M. Fritschy ◽  
M. N. Pangalos ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Inhibitory Synapses ◽  
Receptor Subtypes ◽  
Direct Binding ◽  
Gabaa Receptor Subtypes

scholarly journals Plasmin-mediated cleavage of EphA4 at central amygdala inhibitory synapses controls anxiety

2021 ◽  
Author(s):  
Mariusz Mucha ◽  
Alberto Labrador-Ramos ◽  
Benjamin Attwood ◽  
Malorzata Bajor ◽  
Jaison Kolenchery ◽  
...  
Keyword(s):  
Gaba Receptor ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Receptor Expression ◽  
Inhibitory Synapses ◽  
Tyrosine Kinase Receptor ◽  
Target Cells ◽  
Central Amygdala ◽  
Anchoring Protein ◽  
Fear And Anxiety

Severe stress can trigger complex behavioural changes such as high anxiety (1). Inhibitory GABA-ergic interneurons in the lateral division of the central amygdala (CEl) control anxiety through feedforward inhibition of their target cells in the medial division (CEm) (2, 3). In particular, PKCδ-positive (PKCδ+) interneurons in CEl are critical elements of the neuronal circuitry of fear and anxiety (3-5), but the molecular mechanisms they employ are poorly understood. Here, we show that, during stress, GABA-ergic synapses of amygdala PKCδ+ interneurons are regulated by a serine protease plasmin. On stress, plasmin cleaves the extracellular portion of the tyrosine kinase receptor EphA4 triggering its dissociation from gephyrin, a postsynaptic GABA-receptor anchoring protein. Dynamic EphA4/gephyrin interaction leads to modification of dendritic spine morphology and synaptic GABA-receptor expression profile. Consistent with the critical role for the plasmin/EphA4/gephyrin signalling axis in anxiogenesis, viral delivery of plasmin-resistant (prEphA4) form of EphA4 into the central amygdala prevents the development of stress-induced anxiety in mice, while the delivery of plasmin-truncated EphA4 (tEphA4) dramatically enhances this effect. Thus, our studies identify a novel, critical molecular cascade regulating GABA-ergic signalling in the central amygdala synapses that allows bidirectional switching of animal behaviour from high to low anxiety states.

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The CPZ site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The C C C C C C site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Interactions of tricyclic antipsychotic and antidepressant medications with a novel binding site in GABAA receptors

2021 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Antidepressant Drugs ◽  
Receptor Subtypes ◽  
Specific Information ◽  
Therapeutic Effects ◽  
The Novel ◽  
Antidepressant Medications ◽  
Functional Studies

Background and Purpose: Many psychotherapeutic drugs including clozapine have a polypharmacological profile and act on GABA receptors, where subtype-specific information is often lacking. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit containing GABA receptors. Experimental Approach: Functional studies of GABA modulatory effects by antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Computational ligand analysis complemented the functional and mutational data. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine have negative modulatory effects on multiple GABA receptor subtypes, including α5-containing. On the latter we show negative modulatory effects for five additional antipsychotic and antidepressant drugs. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABA receptor subunits. Conclusion and Implications: Our findings support previous studies suggesting a link between some of the therapeutic effects of clozapine and its negative modulatory action on certain GABA receptor subtypes. The novel site we describe in this study is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology.

On nearly-commensurable periods in the restricted problem of three bodies, with calculations of the long-period variations in the interior 2:1 case

1966 ◽  
Vol 25 ◽  
pp. 197-222 ◽  
Author(s):  
P. J. Message
Keyword(s):  
Periodic Solution ◽  
Periodic Solutions ◽  
Large Amplitude ◽  
Restricted Problem ◽  
Small Amplitude ◽  
Minor Planets ◽  
Long Period ◽  
Numerical Integrations ◽  
Period Variations ◽  
The Mean

An analytical discussion of that case of motion in the restricted problem, in which the mean motions of the infinitesimal, and smaller-massed, bodies about the larger one are nearly in the ratio of two small integers displays the existence of a series of periodic solutions which, for commensurabilities of the typep+ 1:p, includes solutions of Poincaré'sdeuxième sortewhen the commensurability is very close, and of thepremière sortewhen it is less close. A linear treatment of the long-period variations of the elements, valid for motions in which the elements remain close to a particular periodic solution of this type, shows the continuity of near-commensurable motion with other motion, and some of the properties of long-period librations of small amplitude.To extend the investigation to other types of motion near commensurability, numerical integrations of the equations for the long-period variations of the elements were carried out for the 2:1 interior case (of which the planet 108 “Hecuba” is an example) to survey those motions in which the eccentricity takes values less than 0·1. An investigation of the effect of the large amplitude perturbations near commensurability on a distribution of minor planets, which is originally uniform over mean motion, shows a “draining off” effect from the vicinity of exact commensurability of a magnitude large enough to account for the observed gap in the distribution at the 2:1 commensurability.

scholarly journals Heterogeneous expression of GABA receptor‐like subunits LCCH3 and GRD reveals functional diversity of GABA receptors in the honeybee Apis mellifera

2020 ◽  
Vol 177 (17) ◽  
pp. 3924-3940
Author(s):  
Christopher Henry ◽  
Thierry Cens ◽  
Pierre Charnet ◽  
Catherine Cohen‐Solal ◽  
Claude Collet ◽  
...  
Keyword(s):  
Apis Mellifera ◽  
Functional Diversity ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Heterogeneous Expression

Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

2000 ◽  
Vol 84 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Jiu-Lin Du ◽  
Xiong-Li Yang
Keyword(s):  
Subcellular Localization ◽  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Drug Application ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Receptor Subtypes ◽  
Inner Retina ◽  
Axon Terminals ◽  
Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

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