Olfactory Nerve–Evoked, Metabotropic Glutamate Receptor–Mediated Synaptic Responses in Rat Olfactory Bulb Mitral Cells

The group I metabotropic glutamate receptor (mGluR) subtype, mGluR1, is highly expressed on the apical dendrites of olfactory bulb mitral cells and thus may be activated by glutamate released from olfactory nerve (ON) terminals. Previous studies have shown that mGluR1 agonists directly excite mitral cells. In the present study, we investigated the involvement of mGluR1 in ON-evoked responses in mitral cells in rat olfactory bulb slices using patch-clamp electrophysiology. In voltage-clamp recordings, the average EPSC evoked by single ON shocks or brief trains of ON stimulation (six pulses at 50 Hz) in normal physiological conditions were not significantly affected by the nonselective mGluR antagonist LY341495 (50–100 μΜ) or the mGluR1-specific antagonist LY367385 (100 μM); ON-evoked responses were attenuated, however, in a subset (36%) of cells. In the presence of blockers of ionotropic glutamate and GABA receptors, application of the glutamate uptake inhibitors THA (300 μM) and TBOA (100 μM) revealed large-amplitude, long-duration responses to ON stimulation, whereas responses elicited by antidromic activation of mitral/tufted cells were unaffected. Magnitudes of the ON-evoked responses elicited in the presence of THA–TBOA were dependent on stimulation intensity and frequency, and were maximal during high-frequency (50-Hz) bursts of ON spikes, which occur during odor stimulation. ON-evoked responses elicited in the presence of THA–TBOA were significantly reduced or completely blocked by LY341495 or LY367385 (100 μM). These results demonstrate that glutamate transporters tightly regulate access of synaptically evoked glutamate from ON terminals to postsynaptic mGluR1s on mitral cell apical dendrites. Taken together with other findings, the present results suggest that mGluR1s may not play a major role in phasic responses to ON input, but instead may play an important role in shaping slow oscillatory activity in mitral cells and/or activity-dependent regulation of plasticity at ON–mitral cell synapses.

Download Full-text

Regulation of Main Olfactory Bulb Mitral Cell Excitability by Metabotropic Glutamate Receptor mGluR1

Journal of Neurophysiology ◽

10.1152/jn.00349.2004 ◽

2004 ◽

Vol 92 (5) ◽

pp. 3085-3096 ◽

Cited By ~ 43

Author(s):

Thomas Heinbockel ◽

Philip Heyward ◽

François Conquet ◽

Matthew Ennis

Keyword(s):

Olfactory Bulb ◽

Glutamate Receptor ◽

Knockout Mice ◽

Metabotropic Glutamate Receptor ◽

Physiological Role ◽

Olfactory Nerve ◽

Mitral Cell ◽

Main Olfactory Bulb ◽

Metabotropic Glutamate ◽

Group I

In the rodent main olfactory bulb (MOB), mitral cells (MCs) express high levels of the group I metabotropic glutamate receptor (mGluR) subtype, mGluR1. The significance of this receptor in modulating MC excitability is unknown. We investigated the physiological role of mGluR1 in regulating MC activity in rat and mouse MOB slices. The selective group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), but not group II or III agonists, induced potent, dose-dependent, and reversible depolarization and increased firing of MCs. These effects persisted in the presence of blockers of fast synaptic transmission, indicating that they are due to direct activation of mGluRs on MCs. Voltage-clamp recordings showed that DHPG elicited a voltage-dependent inward current consisting of multiple components sensitive to potassium and calcium channel blockade and intracellular calcium chelation. MC excitatory responses to DHPG were absent in mGluR1 knockout mice but persisted in mGluR5 knockout mice. Broad-spectrum LY341495 , MCPG, as well as preferential mGluR1 LY367385 antagonists blocked the excitatory effects of DHPG and also potently modulated MC spontaneous and olfactory nerve-evoked excitability. mGluR antagonists altered spontaneous membrane potential bistability, increasing the duration of the up and down states. mGluR antagonists also substantially attenuated MC responses to sensory input, decreasing the probability and increasing the latency of olfactory nerve-evoked spikes. These findings suggest that endogenous glutamate tonically modulates MC excitability and responsiveness to olfactory nerve input, and hence the operation of the MOB circuitry, via activation of mGluR1.

Download Full-text

Metabotropic Glutamate Receptors in the Main Olfactory Bulb Drive Granule Cell-Mediated Inhibition

Journal of Neurophysiology ◽

10.1152/jn.00884.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 858-870 ◽

Cited By ~ 24

Author(s):

Thomas Heinbockel ◽

Nora Laaris ◽

Matthew Ennis

Keyword(s):

Olfactory Bulb ◽

Metabotropic Glutamate Receptor ◽

Feedback Inhibition ◽

Mitral Cell ◽

Equilibrium Potential ◽

Mitral Cells ◽

Main Olfactory Bulb ◽

Inward Current ◽

Metabotropic Glutamate ◽

Group I

Main olfactory bulb (MOB) granule cells (GCs) express high levels of the group I metabotropic glutamate receptor (mGluR), mGluR5. We investigated the role of mGluRs in regulating GC activity in rodent MOB slices using whole cell patch-clamp electrophysiology. The group I/II mGluR agonist (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (ACPD) or the selective group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) depolarized (∼20 mV) and increased the firing rate of GCs. In the presence of ionotropic glutamate and GABA receptor antagonists, DHPG evoked a more modest depolarization (∼8 mV). In voltage clamp, DHPG, but not group II [(2S,2′R,3)-2-(2′,3′-dicarboxycyclopropyl)glycine, DCG-IV] or group III [L(+)-2-amino-4-phosphonobutyric acid, L-AP4] mGluR agonists, induced an inward current. The inward current reversed polarity near the potassium equilibrium potential, suggesting mediation by closure of potassium channels. The DHPG-evoked inward current was unaffected by the mGluR1 antagonist ( S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), was blocked by the group I/II mGluR antagonist (α S)-α-amino-α-[(1 S,2 S)-2-carboxycyclopropyl]-9H-xanthine-9-propanoic acid (LY341495), and was absent in GCs from mGluR5 knockout mice. LY341495 also attenuated mitral cell-evoked voltage-sensitive dye signals in the external plexiform layer and mitral cell-evoked spikes in GCs. These results suggest that activation of mGluR5 increases GC excitability, an effect that should increase GC-mediated GABAergic inhibition of mitral cells. In support of this: DHPG increased the frequency of spontaneous GABAergic inhibitory postsynaptic currents in mitral cells and LY341495 attenuated the feedback GABAergic postsynaptic potential elicited by intracellular depolarization of mitral cells. Our results suggest that activation of mGluR5 participates in feedforward and/or feedback inhibition at mitral cell to GC dendrodendritic synapses, possibly to modulate lateral inhibition and contrast in the MOB.

Download Full-text

Group I Metabotropic Glutamate Receptors Are Differentially Expressed by Two Populations of Olfactory Bulb Granule Cells

Journal of Neurophysiology ◽

10.1152/jn.01202.2006 ◽

2007 ◽

Vol 97 (4) ◽

pp. 3136-3141 ◽

Cited By ~ 8

Author(s):

Thomas Heinbockel ◽

Kathryn A. Hamilton ◽

Matthew Ennis

Keyword(s):

Olfactory Bulb ◽

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Granule Cells ◽

Mitral Cell ◽

Mitral Cells ◽

Patch Clamp Recording ◽

Metabotropic Glutamate ◽

Group I ◽

Bath Application

In the main olfactory bulb, several populations of granule cells (GCs) can be distinguished based on the soma location either superficially, interspersed with mitral cells within the mitral cell layer (MCL), or deeper, within the GC layer (GCL). Little is known about the physiological properties of superficial GCs (sGCs) versus deep GCs (dGCs). Here, we used patch-clamp recording methods to explore the role of Group I metabotropic glutamate receptors (mGluRs) in regulating the activity of GCs in slices from wildtype and mGluR−/− mutant mice. In wildtype mice, bath application of the selective Group I mGluR agonist DHPG depolarized and increased the firing rate of both GC subtypes. In the presence of blockers of fast synaptic transmission (APV, CNQX, gabazine), DHPG directly depolarized both GC subtypes, although the two GC subtypes responded differentially to DHPG in mGluR1−/− and mGluR5−/− mice. DHPG depolarized sGCs in slices from mGluR5−/− mice, although it had no effect on sGCs in slices from mGluR1−/− mice. By contrast, DHPG depolarized dGCs in slices from mGluR1−/− mice but had no effect on dGCs in slices from mGluR5−/− mice. Previous studies showed that mitral cells express mGluR1 but not mGluR5. The present results therefore suggest that sGCs are more similar to mitral cells than dGCs in terms of mGluR expression.

Download Full-text

Developmental regulation of metabotropic glutamate receptor 1 splice variants in olfactory bulb mitral cells

Journal of Neuroscience Research ◽

10.1002/jnr.21864 ◽

2009 ◽

Vol 87 (2) ◽

pp. 369-379 ◽

Cited By ~ 3

Author(s):

P. Bovolin ◽

S. Bovetti ◽

A. Fasolo ◽

Z. Katarova ◽

G. Szabo ◽

...

Keyword(s):

Olfactory Bulb ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Splice Variants ◽

Developmental Regulation ◽

Mitral Cells ◽

Metabotropic Glutamate ◽

Metabotropic Glutamate Receptor 1

Download Full-text

Excitatory Actions of Noradrenaline and Metabotropic Glutamate Receptor Activation in Granule Cells of the Accessory Olfactory Bulb

Journal of Neurophysiology ◽

10.1152/jn.91093.2008 ◽

2009 ◽

Vol 102 (2) ◽

pp. 1103-1114 ◽

Cited By ~ 23

Author(s):

Richard S. Smith ◽

Christopher J. Weitz ◽

Ricardo C. Araneda

Keyword(s):

Olfactory Bulb ◽

Receptor Antagonist ◽

Glutamate Receptor ◽

Adrenergic Receptor ◽

Metabotropic Glutamate Receptor ◽

Granule Cells ◽

Mitral Cells ◽

Accessory Olfactory Bulb ◽

Metabotropic Glutamate ◽

Excitatory Action

Modulation of dendrodendritic synapses by the noradrenergic system in the accessory olfactory bulb (AOB) plays a key role in the formation of memory in olfactory-mediated behaviors. We have recently shown that noradrenaline (NA) inhibits mitral cells by increasing γ-aminobutyric acid inhibitory input onto mitral cells in the AOB, suggesting an excitatory action of NA on granule cells (GCs). Here, we show that NA (10 μM) elicits a long-lasting depolarization of GCs. This effect is mediated by activation of α1-adrenergic receptors as the depolarization is mimicked by phenylephrine (PE, 30 μM) and completely blocked by the α1-adrenergic receptor antagonist prazosin (300 nM). In addition to this depolarization, application of NA induced the appearance of a slow afterdepolarization (sADP) following a stimulus-elicited train of action potentials. Similarly, the group I metabotropic glutamate receptor (mGluR1) agonist DHPG (10–30 μM) also produced a depolarization of GCs and the appearance of a stimulus-induced sADP. The ionic and voltage dependence and sensitivity to blockers of the sADP suggest that it is mediated by the nonselective cationic conductance ICAN. Thus the excitatory action resulting from the activation of these receptors could be mediated by a common transduction target. Surprisingly, the excitatory effect of PE on GCs was completely blocked by the mGluR1 antagonist LY367385 (100 μM). Conversely, the effect of DHPG was not antagonized by the α1-adrenergic receptor antagonist prazosin (300 nM). These results suggest that most of the noradrenergic effect on GCs in the AOB is mediated by potentiation of a basal activity of mGluR1s.

Download Full-text

Metabotropic Glutamate Receptor Agonists Alter Neuronal Excitability and Ca2+ Levels via the Phospholipase C Transduction Pathway in Cultured Purkinje Neurons

Journal of Neurophysiology ◽

10.1152/jn.1997.78.1.63 ◽

1997 ◽

Vol 78 (1) ◽

pp. 63-75 ◽

Cited By ~ 49

Author(s):

Jeffrey G. Netzeband ◽

Kathy L. Parsons ◽

Dan D. Sweeney ◽

Donna L. Gruol

Keyword(s):

Phospholipase C ◽

Glutamate Receptor ◽

Neuronal Excitability ◽

Metabotropic Glutamate Receptor ◽

Purkinje Neurons ◽

Transduction Pathway ◽

Electrophysiological Response ◽

Metabotropic Glutamate ◽

Group I ◽

Intracellular Ca

Netzeband, Jeffrey G., Kathy L. Parsons, Dan D. Sweeney, and Donna L. Gruol. Metabotropic glutamate receptor agonists alter neuronal excitability and Ca2+ levels via the phospholipase C transduction pathway in cultured Purkinje neurons. J. Neurophysiol. 78: 63–75, 1997. Selective agonists for metabotropic glutamate receptor (mGluR) subtypes were tested on mature, cultured rat cerebellar Purkinje neurons (≥21 days in vitro) to identify functionally relevant mGluRs expressed by these neurons and to investigate the transduction pathways associated with mGluR-mediated changes in membrane excitability. Current-clamp recordings (nystatin/perforated-patch method) were used to measure the membrane response of Purkinje neurons to brief microperfusion pulses (1.5 s) of the group I (mGluR1/mGluR5) agonists (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid (300 μM), quisqualate (5 μM), and ( R,S)-3,5-dihydroxyphenylglycine (50–500 μM). All group I mGluR agonists elicited biphasic membrane responses and burst activity in the Purkinje neurons. In addition, the group I mGluR agonists produced alterations in the active membrane properties of the Purkinje neurons and depressed the off response after hyperpolarizing current injection. In parallel microscopic Ca2+ imaging experiments, application of the group I mGluR agonists to fura-2-loaded cells elicited increases in intracellular Ca2+ in both the somatic and dendritic regions. The group II (mGluR2/mGluR3) agonist (2 S,3 S,4 S)-α-(carboxycyclopropyl)-glycine (10 μM) and the group III (mGluR4/mGluR6/mGluR7/mGluR8) agonists l(+)-2-amino-4-phosphonobutyric acid (1 mM) and O-phospho-l-serine (200 μM) had no effect on the membrane potential or intracellular Ca2+ levels of the Purkinje neurons. The cultured Purkinje neurons, but not granule neurons or interneurons, showed immunostaining for mGluR1α in both the somatic and dendritic regions. All effects of the group I mGluR agonists were blocked by (+)-α-methyl-4-carboxyphenylglycine (1 mM), an mGluR antagonist. Furthermore, the phospholipase C inhibitor 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (2 μM) blocked the group I mGluR agonist-mediated electrophysiological response and greatly attenuated the Ca2+ signal elicited by group I mGluR agonists, particularly in the dendrites. The inactive analogue1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]2,5-pyrrolidine-dione (2 μM) was relatively ineffective against the electrophysiological response and Ca2+ signal. These results indicate that functional group I mGluRs (but not group II or III mGluRs) can be activated on mature Purkinje neurons in culture and result in changes in neuronal excitability and intracellular Ca2+ mediated through phospholipase C. These data obtained from a defined neuronal type, the Purkinje neuron, confirm biochemical and molecular studies on the transduction mechanisms of group I mGluRs and show that this transduction pathway is linked to neuronal excitability and intracellular Ca2+ release in the Purkinje neurons.

Download Full-text