Epileptogenesis Up-Regulates Metabotropic Glutamate Receptor Activation of Sodium-Calcium Exchange Current in the Amygdala

2000 ◽  
Vol 83 (4) ◽  
pp. 2458-2462 ◽  
Author(s):  
N. Bradley Keele ◽  
Fatiha Zinebi ◽  
Volker Neugebauer ◽  
P. Shinnick-Gallagher
Keyword(s):  
Basolateral Amygdala ◽  
Metabotropic Glutamate Receptor ◽  
Partial Agonist ◽  
Brain Slices ◽  
Receptor Activation ◽  
Exchange Current ◽  
Inward Current ◽  
Mglu Receptor ◽  
Metabotropic Glutamate ◽  
Group I

Postsynaptic metabotropic glutamate (mGlu) receptor-activated inward current mediated by Na+-Ca2+ exchange was compared in basolateral amygdala (BLA) neurons from brain slices of control (naı̈ve and sham-operated) and amygdala-kindled rats. In control neurons, the mGlu agonist, quisqualate (QUIS; 1–100 μM), evoked an inward current not associated with a significant change in membrane slope conductance, measured from current-voltage relationships between −110 and −60 mV, consistent with activation of the Na+-Ca2+ exchanger. Application of the group I selective mGlu receptor agonist ( S)-3,5-dihydroxyphenylglycine [( S)-DHPG; 10–1000 μM] or the endogenous agonist, glutamate (10–1000 μM), elicited the exchange current. QUIS was more potent than either ( S)-DHPG or glutamate (apparent EC50 = 19 μM, 57 μM, and 0.6 mM, respectively) in activating the Na+-Ca2+ exchange current. The selective mGlu5 agonist, ( R,S)-2-chloro-5-hydroxyphenylglycine [( R,S)-CHPG; apparent EC50 = 2.6 mM] also induced the exchange current. The maximum response to ( R,S) -DHPG was about half of that of the other agonists suggesting partial agonist action. Concentration-response relationships of agonist-evoked inward currents were compared in control neurons and in neurons from kindled animals. The maximum value for the concentration-response relationship of the partial agonist ( S)-DHPG- (but not the full agonist- [QUIS or ( R, S)-CHPG]) induced inward current was shifted upward suggesting enhanced efficacy of this agonist in kindled neurons. Altogether, these data are consistent with a kindling-induced up-regulation of a group I mGlu-, possibly mGlu5-, mediated responses coupled to Na+-Ca2+ exchange in BLA neurons.

Modulation of Multiple Potassium Currents by Metabotropic Glutamate Receptors in Neurons of the Hypothalamic Supraoptic Nucleus

1997 ◽  
Vol 78 (6) ◽  
pp. 3428-3437 ◽  
Author(s):  
L. A. Schrader ◽  
J. G. Tasker
Keyword(s):  
Glutamate Receptors ◽  
Supraoptic Nucleus ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Outward Current ◽  
Magnocellular Neurons ◽  
Inward Current ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group I

Schrader, L. A. and J. G. Tasker. Modulation of multiple potassium currents by metabotropic glutamate receptors in neurons of the hypothalamic supraoptic nucleus. J. Neurophysiol. 78: 3428–3437, 1997. We studied the effects of activation of the metabotropic glutamate receptors on intrinsic currents of magnocellular neurons of the supraoptic nucleus (SON) with whole cell patch-clamp and conventional intracellular recordings in coronal slices (400 μm) of the rat hypothalamus. Trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid ( trans-ACPD, 10–100 μM), a broad-spectrum metabotropic glutamate receptor agonist, evoked an inward current (18.7 ± 3.45 pA) or a slow depolarization (7.35 ± 4.73 mV) and a 10–30% decrease in whole cell conductance in ∼50% of the magnocellular neurons recorded at resting membrane potential. The decrease in conductance and the inward current were caused largely by the attenuation of a resting potassium conductance because they were reduced by the replacement of intracellular potassium with an equimolar concentration of cesium or by the addition of potassium channel blockers to the extracellular medium. In some cells, trans-ACPD still elicited a small inward current after blockade of potassium currents, which was abolished by the calcium channel blocker, CdCl2. Trans-ACPD also reduced voltage-gated and Ca2+-activated K+ currents in these cells. Trans-ACPD reduced the transient outward current ( I A) by 20–70% and/or the I A-mediated delay to spike generation in ∼60% of magnocellular neurons tested. The cells that showed a reduction of I A generally also showed a 20–60% reduction in a voltage-gated, sustained outward current. Finally, trans-ACPD attenuated the Ca2+-dependent outward current responsible for the afterhyperpolarization ( I AHP) in ∼60% of cells tested. This often revealed an underlying inward current thought to be responsible for the depolarizing afterpotential seen in some magnocellular neurons. (RS)-3,5-dihydroxyphenylglycine, a group I receptor-selective agonist, mimicked the effects of trans-ACPD on the resting and voltage-gated K+ currents. (RS)-α-methyl-4-carboxyphenylglycine, a group I/II metabotropic glutamate receptor antagonist, blocked these effects. A group II receptor agonist, 2S,1′S,2′S-2carboxycyclopropylglycine and a group III receptor agonist, l(+)-2-amino-4-phosphonobutyric acid, had no effect on the resting or voltage-gated K+ currents, indicating that the reduction of K+ currents was mediated by group I receptors. About 80% of the SON cells that were labeled immunohistochemically for vasopressin responded to metabotropic glutamate receptor activation, whereas only 33% of labeled oxytocin cells responded, suggesting that metabotropic receptors are expressed preferentially in vasopressinergic neurons. These data indicate that activation of the group I metabotropic glutamate receptors leads to an increase in the postsynaptic excitability of magnocellular neurons by blocking resting K+ currents as well as by reducing voltage-gated and Ca2+-activated K+ currents.

Loss of mGluR-mediated hyperpolarizations and increase in mGluR depolarizations in basolateral amygdala neurons in kindling-induced epilepsy

1996 ◽  
Vol 76 (4) ◽  
pp. 2808-2812 ◽  
Author(s):  
K. H. Holmes ◽  
N. B. Keele ◽  
P. Shinnick-Gallagher
Keyword(s):  
Basolateral Amygdala ◽  
Metabotropic Glutamate Receptor ◽  
Maximum Amplitude ◽  
Outward Current ◽  
Response Relationship ◽  
Inward Current ◽  
Group I ◽  
Hyperpolarizing Response ◽  
Group Ii

1. Intracellular recordings were made from neurons of the basolateral amygdala (BLA) in in vitro slice preparations to determine long-term differences in metabotropic glutamate receptor (mGluR) agonist-induced membrane responses in control and amygdala-kindled rats. 2. (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine-1 (L-CCG-I; 100 microM) typically evoked a hyperpolarization/outward current in control BLA neurons; the hyperpolarization is mediated through a group-II-like mGluR subtype of receptor and is recorded in accommodating neurons that cease firing in the presence of a long (400 ms) depolarizing current injection (0.5 nA). In amygdala-kindled slices, L-CCG-I (100 microM) hyperpolarized only 1 of 13 BLA neurons. 3. 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) (100 microM) elicited a hyperpolarization/depolarization (outward/inward current) in control neurons and evoked only a membrane depolarization (inward current) in kindled BLA neurons; this depolarization is similar to that mediated by group I mGluR activation in other neurons. 4. In control nonaccommodating neurons the concentration-response relationship for the 1S,3R-ACPD-induced inward current had a median effective concentration (EC50) of 49 microM and a maximum amplitude of 182 +/- 30 (mean +/- SE) pA. In kindled nonaccommodating neurons the EC50 of the concentration-response relationship for 1S,3R-ACPD was shifted to 29 microM and the maximum value increased to 265 +/- 15 pA, reflecting an increase in efficacy. 5. These data suggest that amygdala kindling causes lasting changes in mGluR responses in the BLA reflecting a downregulation of a group-II-like mGluR subtype mediating the hyperpolarizing response and an upregulation of a group I mGluR1 or 5 subtype. The hyperpolarizing response reduced by kindling and the increase in the group I mGluR response may reflect an alteration in the balance between inhibition and excitation and may contribute to the transition to epileptiform bursting in kindled neurons.

Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability

1995 ◽  
Vol 74 (1) ◽  
pp. 122-129 ◽  
Author(s):  
R. W. Gereau ◽  
P. J. Conn
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Brain Slices ◽  
Second Messenger ◽  
Receptor Subtypes ◽  
Bhk Cells ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Group Ii

1. Metabotropic glutamate receptors (mGluRs) are coupled to various second-messenger systems through guanosine 5'-triphosphate-binding proteins. To date, at least seven mGluRs have been cloned, and these mGluR subtypes can be divided into three major groups on the basis of similarities in amino acid sequence, coupling to second-messenger cascades in expression systems, and pharmacological profiles. These groups include group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, and mGluR7). 2. On the basis of its selective activation of phosphoinositide hydrolysis in brain slices and its ability to activate mGluR1a expressed in Xenopus oocytes, others have suggested that 3.5-dihydroxyphenylglycine (DHPG) may be selective for group I mGluRs. Consistent with this hypothesis, we report that DHPG also activates mGluR5 expressed in oocytes, whereas it is inactive at mGluR4 and mGluR7 expressed in baby hamster kidney (BHK) cells. The compound (2S,1'R,2'R,3'R)-2-(2.3-dicarboxycyclopropyl)glycine (DCG-IV) activates both mGluR2 and mGluR3 at submicromolar concentrations, whereas it is inactive at mGluR4 and mGluR1, suggesting that this compound may be selective for group II mGluRs. Consistent with this hypothesis, we find that DCG-IV does not activate mGluR5 expressed in oocytes and does not activate mGluR7 expressed in BHK cells. These findings suggest that DHPG and DCG-IV are highly selective agonists for group I and group II mGluRs, respectively. 3. Previous studies that have examined the physiological roles of mGluRs have generally used agonists that do not differentiate between the various subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Distinct Roles of Metabotropic Glutamate Receptor Activation on Inhibitory Signaling in the Ventral Lateral Geniculate Nucleus

2009 ◽  
Vol 101 (4) ◽  
pp. 1761-1773 ◽  
Author(s):  
G. Govindaiah ◽  
Charles L. Cox
Keyword(s):  
Lateral Geniculate Nucleus ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Brightness Discrimination ◽  
Optic Tract ◽  
Gaba Release ◽  
Receptor Activation ◽  
Metabotropic Glutamate ◽  
Lateral Geniculate ◽  
Group I

The ventral lateral geniculate nucleus (vLGN) has been implicated in numerous functions including circadian rhythms, brightness discrimination, pupillary light reflex, and other visuomotor functions. The contribution of inhibitory mechanisms in the regulation of vLGN neuron excitability remains unexplored. We examined the actions of metabotropic glutamate receptor (mGluR) activation on the intrinsic excitability and inhibitory synaptic transmission in different lamina of vLGN. Activation of mGluRs exerts distinct pre- and postsynaptic actions in vLGN neurons. In the lateral magnocellular subdivision of vLGN (vLGNl), the general mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) enhanced the frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSC) that persisted in the presence of sodium channel blocker tetrodotoxin (TTX) in a subpopulation of neurons (TTX insensitive). This increase is attributed to the increased output of dendritic GABA release from vLGN interneurons. In contrast, in the medial subdivision of vLGN (vLGNm), the mGluR agonist-mediated increase in sIPSC frequency was completely blocked by TTX. The selective Group I mGluR agonist ( RS)-3,5-dihydroxyphenylglycine (DHPG) increased sIPSC frequency, whereas the selective Group II mGluR agonist (2 R, 4 R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly decreased sIPSC frequency in vLGNl neurons. Optic tract stimulation also produced an mGluR-dependent increase in sIPSC frequency in vLGNl neurons. In contrast, we were unable to synaptically evoke alterations in sIPSC activity in vLGNm neurons. In addition to these presynaptic actions, DHPG depolarized both vLGNl and vLGNm neurons. In vLGN interneurons, mGluR activation produced opposing actions: APDC hyperpolarized the membrane potential, whereas DHPG produced a membrane depolarization. The present findings demonstrate diverse actions of mGluRs on vLGN neurons localized within different vLGN lamina. Considering these different lamina are coupled with distinct functional roles, thus these diverse actions may be involved in distinctive forms of visual and visuomotor information processing.

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