Biphasic Modulation of GABA Release From Stellate Cells by Glutamatergic Receptor Subtypes

2007 ◽  
Vol 98 (1) ◽  
pp. 550-556 ◽  
Author(s):  
Siqiong June Liu
Keyword(s):  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Gaba Release ◽  
Stellate Cells ◽  
Climbing Fibers ◽  
Receptor Subtypes ◽  
Presynaptic Terminals ◽  
Parallel Fibers ◽  
Release Probability ◽  
Basket Cells

The release of inhibitory transmitters from CNS neurons can be modulated by ionotropic glutamate receptors that are present in the presynaptic terminals. In the cerebellum, glutamate released from climbing fibers (but not from parallel fibers) activates presynaptic AMPA receptors and suppresses the release of the inhibitory transmitter GABA from basket cells onto postsynaptic Purkinje cells. This input-specific modulation has been attributed to the close proximity of the climbing fibers to the axons of the basket cells. Our recent work indicates that glutamate released from parallel fibers can “spill over” and reach the axons of stellate cells. Here I test the possibility that this spillover glutamate can activate presynaptic AMPA receptors in stellate cells and in this way modulate their release of GABA. I find that stimulation of parallel fibers activates AMPA receptors and transiently suppresses autoreceptor and autaptic GABAergic currents in stellate cells. Activation of AMPA receptors reduces the release of GABA and the suppression occurs more frequently in immature cells that have a high release probability. By contrast the release of GABA from mature stellate cells that have a low release probability is potentiated by the activation of NMDA-type glutamate receptors on presynaptic terminals. Thus during development, the glutamatergic modulation of GABA release switches from an AMPA-receptor–mediated transient suppression to a NMDA-receptor–induced lasting potentiation.

Presynaptic Modulation by Metabotropic Glutamate Receptors of Excitatory and Inhibitory Synaptic Inputs to Hypothalamic Magnocellular Neurons

1997 ◽  
Vol 77 (2) ◽  
pp. 527-527 ◽  
Author(s):  
L. A. Schrader ◽  
J. G. Tasker
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Gaba Release ◽  
Metabotropic Receptors ◽  
Presynaptic Terminals ◽  
Magnocellular Neurons ◽  
Group Iii ◽  
Synaptic Inputs ◽  
Metabotropic Glutamate ◽  
Group I

Schrader, L. A. and J. G. Tasker. Presynaptic modulation by metabotropic glutamate receptors of excitatory and inhibitory synaptic inputs to hypothalamic magnocellular neurons. J. Neurophysiol. 77: 527–536, 1997. The effects of activation of metabotropic glutamate receptors (mGluRs) on synaptic inputs to magnocellular neurons of the hypothalamic supraoptic nucleus (SON) were studied with the use of whole cell patch-clamp and microelectrode recordings in acute hypothalamic slices. Application of the mGluR agonist trans-(±)-1-amino-1,3-cyclopentane dicarboxylic acid ( trans-ACPD, 100 μM) elicited an increase in the frequency of spontaneous excitatory postsynaptic potentials (EPSPs) and excitatory postsynaptic currents (EPSCs) in 20% of the cells, and of spontaneous inhibitory postsynaptic potentials (IPSPs) and inhibitory postsynaptic currents (IPSCs) in 50% of the cells tested in normal medium. The increased frequency of spontaneous EPSPs/EPSCs and IPSPs/IPSCs was blocked by tetrodotoxin (TTX), indicating that mGluRs act to excite the somata/dendrites of presynaptic glutamatergic and GABAergic neurons. (RS)-3,5-dihydroxyphenylglycine (50 μM), a selective group I receptor agonist, mimicked the presynaptic somatic/dendritic effects of trans-ACPD, suggesting that the presynaptic somatic/dendritic receptors responsible for increased spike-dependent glutamate and γ-aminobutyric acid (GABA) release belong to the group I mGluRs. In the presence of TTX, trans-ACPD caused a decrease in the frequency of miniature EPSCs (up to 90%) in 13 of 16 cells, and a decrease in the frequency of miniature IPSCs (up to 80%) in 10 of 16 cells tested. Miniature EPSC and IPSC amplitudes usually did not change in trans-ACPD, suggesting that activation of metabotropic receptors located at presynaptic glutamatergic and GABAergic terminals led to a reduction in transmitter release onto SON magnocellular neurons. l(+)-2-amino-4-phosphonobutyric acid (100–250 μM), a selective group III receptor agonist, mimicked the effects of trans-ACPD at presynaptic terminals, decreasing the frequency of miniature EPSCs and IPSCs by up to 85% without affecting their amplitude. Thus the metabotropic receptors at presynaptic glutamate and GABA terminals in the SON belong to group III mGluRs. EPSCs evoked by electrical stimulation were enhanced by the group III receptor antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid, suggesting that presynaptic metabotropic receptors are activated by the release of endogenous glutamate. These data indicate that mGluRs in the hypothalamus have opposing actions at presynaptic somata/dendrites and at presynaptic terminals. Activation of group I receptors (mGluR1 and/or mGluR5) on presynaptic somata/dendrites led to an increase in spike-dependent transmitter release, whereas activation of the group III receptors (mGluR4, 7, and/or 8) on presynaptic terminals suppressed glutamate and GABA release onto SON neurons. No diffferences were seen in the effects of mGluR activation between immunohistochemically identified oxytocin and vasopressin neurons of the SON.

scholarly journals Modulated discharge of Purkinje and stellate cells persists after unilateral loss of vestibular primary afferent mossy fibers in mice

2013 ◽  
Vol 110 (10) ◽  
pp. 2257-2274 ◽  
Author(s):  
N. H. Barmack ◽  
V. Yakhnitsa
Keyword(s):  
Purkinje Cells ◽  
Stellate Cell ◽  
Mossy Fibers ◽  
Stellate Cells ◽  
Climbing Fibers ◽  
Afferent Pathways ◽  
Parallel Fibers ◽  
Primary Afferent ◽  
Low Frequencies ◽  
Cell Discharge

Cerebellar Purkinje cells are excited by two afferent pathways: climbing and mossy fibers. Climbing fibers evoke large “complex spikes” (CSs) that discharge at low frequencies. Mossy fibers synapse on granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of “simple spikes” (SSs). Both afferent systems convey vestibular information to folia 9c–10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8–10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c–10, to which vestibular primary afferents project, and in folia 8–9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL-induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In summary, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. Whereas vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the nonspecific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers.

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

Selective Inhibition of Spontaneous But Not Ca2+-Dependent Release Machinery by Presynaptic Group II mGluRs in Rat Cerebellar Slices

2006 ◽  
Vol 96 (1) ◽  
pp. 86-96 ◽  
Author(s):  
Maike Glitsch
Keyword(s):  
Action Potential ◽  
Glutamate Receptors ◽  
Neurotransmitter Release ◽  
Metabotropic Glutamate Receptors ◽  
Gaba Release ◽  
Spontaneous Release ◽  
Metabotropic Receptors ◽  
Voltage Gated ◽  
Metabotropic Glutamate ◽  
Group Ii

Two main forms of neurotransmitter release are known: action potential-evoked and spontaneous release. Action potential-evoked release depends on Ca2+entry through voltage-gated Ca2+channels, whereas spontaneous release is thought to be Ca2+-independent. Generally, spontaneous and action potential-evoked release are believed to use the same release machinery to release neurotransmitter. This study shows, using the whole cell patch-clamp technique in rat cerebellar slices, that at the interneuron- Purkinje cell synapse activation of presynaptic group II metabotropic glutamate receptors suppresses spontaneous GABA release through a mechanism independent of voltage-gated Ca2+channels, store-operated Ca2+channels, and Ca2+release from intracellular Ca2+stores, suggesting that the metabotropic receptors target the release machinery directly. Voltage gated Ca2+channel-independent release following increased presynaptic cAMP production is similarly inhibited by these metabotropic receptors. In contrast, both voltage-gated Ca2+channel-dependent and presynaptic N-methyl-d-aspartate receptor-dependent GABA release were unaffected by activation of group II metabotropic glutamate receptors. Hence, the mechanisms underlying spontaneous and Ca2+-dependent GABA release are distinct in that only the former is blocked by group II metabotropic glutamate receptors. Thus the same neurotransmitter, glutamate, can activate or inhibit neurotransmitter release by selecting different receptors that target different release machineries.

scholarly journals NTS adenosine A2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism

2015 ◽  
Vol 309 (1) ◽  
pp. H185-H197 ◽  
Author(s):  
Zeljka Minic ◽  
Donal S. O'Leary ◽  
Tadeusz J. Scislo
Keyword(s):  
Gaba Release ◽  
Right Atrial ◽  
Receptor Subtypes ◽  
Glutamatergic Transmission ◽  
Inhibitory Neurotransmitter ◽  
A2a Receptors ◽  
Cgs 21680 ◽  
Before And After ◽  
Adenosine A2a ◽  
Stimulation Of

Adenosine is a powerful central neuromodulator acting via opposing A1 (inhibitor) and A2a (activator) receptors. However, in the nucleus of the solitary tract (NTS), both adenosine receptor subtypes attenuate cardiopulmonary chemoreflex (CCR) sympathoinhibition of renal, adrenal, and lumbar sympathetic nerve activity and attenuate reflex decreases in arterial pressure and heart rate. Adenosine A1 receptors inhibit glutamatergic transmission in the CCR pathway, whereas adenosine A2a receptors most likely facilitate release of an unknown inhibitory neurotransmitter, which, in turn, inhibits the CCR. We hypothesized that adenosine A2a receptors inhibit the CCR via facilitation of GABA release in the NTS. In urethane-chloralose-anesthetized rats ( n = 51), we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (1–8 μg/kg) before and after selective stimulation of NTS adenosine A2a receptors [microinjections into the NTS of CGS-21680 (20 pmol/50 nl)] preceded by blockade of GABAA or GABAB receptors in the NTS [bicuculline (10 pmol/100 nl) or SCH-50911 (1 nmol/100 nl)]. Blockade of GABAA receptors virtually abolished adenosine A2a receptor-mediated inhibition of the CCR. GABAB receptors had much weaker but significant effects. These effects were similar for the different sympathetic outputs. We conclude that stimulation of NTS adenosine A2a receptors inhibits CCR-evoked hemodynamic and regional sympathetic reflex responses via a GABA-ergic mechanism.

Distal Versus Proximal Inhibitory Shaping of Feedback Excitation in the Electrosensory Lateral Line Lobe: Implications for Sensory Filtering

1998 ◽  
Vol 80 (6) ◽  
pp. 3214-3232 ◽  
Author(s):  
Neil J. Berman ◽  
Leonard Maler
Keyword(s):  
Lateral Line ◽  
Pyramidal Cell ◽  
Stellate Cell ◽  
Molecular Layer ◽  
Pyramidal Cells ◽  
Stellate Cells ◽  
Decay Phase ◽  
Tetanic Stimulation ◽  
Parallel Fibers ◽  
Cell Inhibition

Berman, Neil J. and Leonard Maler. Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering. J. Neurophysiol. 80: 3214–3232, 1998. The inhibition controlling the indirect descending feedback (parallel fibers originating from cerebellar granule cells in the eminentia posterior pars granularis) to electrosensory lateral line lobe (ELL) pyramidal cells was studied using intracellular recording techniques in vitro. Parallel fibers (PF) contact stellate cells and dendrites of ventral molecular layer (VML) GABAergic interneurons. Stellate cells provide local input to pyramidal cell distal dendrites, whereas VML cells contact their somata and proximal dendrites. Single-pulse stimulation of PF evoked graded excitatory postsynaptic potentials (EPSPs) that were blocked by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate (NMDA) antagonists. The EPSPs peaked at 6.4 ± 1.8 ms (mean ± SE; n = 11) but took >50 ms to decay completely. Tetanic stimulation (100 ms, 100 Hz) produced a depolarizing wave with individual EPSPs superimposed. The absolute amplitude of the individual EPSPs decreased during the train. Spike rates, established by injected current, mostly were increased, but in some cells were decreased, by tetanic stimulation. Global application of a γ-aminobutyric acid-A (GABAA) antagonist to the recorded cell's soma and apical dendritic region increased the EPSP peak and decay phase amplitudes. Tetanic stimulation always increased current-evoked spike rates after GABAA blockade during, and for several hundred milliseconds after, the stimulus. Application of a GABAB antagonist did not have any significant effects on the PF-evoked response. This, and the lack of any long hyperpolarizing inhibitory postsynaptic potentials, suggests that VML and stellate cell inhibition does not involve GABAB receptors. Focal GABAA antagonist applications to the dorsal molecular layer (DML) and pyramidal cell layer (PCL) had contrasting effects on PF-evoked EPSPs. DML GABAA blockade significantly increased the EPSP peak amplitude but not the decay phase of the EPSP, whereas PCL GABAA-blockade significantly increased the decay phase, but not the EPSP peak, amplitude. The order of antagonist application did not affect the outcome. On the basis of the known circuitry of the ELL, we conclude that the distal inhibition originated from GABAergic molecular layer stellate cells and the proximal inhibition originated from GABAergic cells of the ventral molecular layer (VML cells). Computer modeling of distal and proximal inhibition suggests that intrinsic differences in IPSP dynamics between the distal and proximal sites may be amplified by voltage-dependent NMDA receptor and persistent sodium currents. We propose that the different time courses of stellate cell and VML cell inhibition allows them to act as low- and high-pass filters respectively on indirect descending feedback to ELL pyramidal cells.

scholarly journals IQSEC2-Associated Intellectual Disability and Autism

2019 ◽  
Vol 20 (12) ◽  
pp. 3038 ◽  
Author(s):  
Nina S. Levy ◽  
George K. E. Umanah ◽  
Eli J. Rogers ◽  
Reem Jada ◽  
Orit Lache ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Nmda Receptors ◽  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Neuronal Development ◽  
Catalytic Domain ◽  
Excitatory Synapses ◽  
Ampa Receptor Subunit ◽  
Ion Influx

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism.

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