Ca2+-dependent depolarization and burst firing of rat CA1 pyramidal neurones induced by N-methyl-D-aspartic acid and quinolinic acid: antagonism by 2-amino-5-phosphonovaleric and kynurenic acids

The excitatory effects of microiontophoretically applied quisqualic (QUIS), N-methyl-D-aspartic (NMDA), and quinolinic (QUIN) acids were investigated using intracellular recording from CA1 pyramidal neurones in slices of rat hippocampus. QUIS evoked only simple action potentials superimposed upon a depolarization which attained a clear plateau. When this level had been reached, increased ejecting currents did not produce further depolarization. By contrast, with low currents NMD A and QUIN elicited small membrane depolarizations which triggered bursts of action potentials superimposed upon rhythmically occurring depolarizing shifts. Larger currents caused depolarization which if sufficiently large completely blocked spike activity. Tetrodotoxin (TTX) prevented the spikes evoked by QUIS and the bursts of action potentials seen with NMDA and QUIN, and the rhythmic depolarizing shifts then appeared as broad spikes of up to 50 mV in amplitude. These and the underlying membrane depolarization were blocked by Co2+, by the NMDA antagonist D(−)-2-amino-5-phosphonovaleric acid (DAPV), and by kynurenic acid (KYNU). It thus appears that the depolarization and burst firing of rat CA1 pyramidal neurones elicited by NMDA and QUIN are Ca2+ dependent while the actions of QUIS are not.

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Actions of kynurenic acid and quinolinic acid in the rat hippocampus in vivo

Experimental Neurology ◽

10.1016/0014-4886(85)90072-x ◽

1985 ◽

Vol 88 (3) ◽

pp. 570-579 ◽

Cited By ~ 58

Author(s):

M.N. Perkins ◽

T.W. Stone

Keyword(s):

Quinolinic Acid ◽

Kynurenic Acid ◽

Rat Hippocampus

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N-cholinergic facilitation of glutamate release from an individual retinotectal fiber in frog

Visual Neuroscience ◽

10.1017/s0952523801184051 ◽

2001 ◽

Vol 18 (4) ◽

pp. 549-558 ◽

Cited By ~ 16

Author(s):

A. KURAS ◽

N. GUTMANIENĖ

Keyword(s):

Nicotinic Acetylcholine Receptors ◽

Action Potentials ◽

Acetylcholine Receptors ◽

Kynurenic Acid ◽

Glutamate Release ◽

Synaptic Potentials ◽

Lower Vertebrates ◽

Optic Fibers ◽

Retinotectal Transmission

Nicotinic acetylcholine receptors are localized on retinotectal axons' terminals in lower vertebrates. The effects of activation of these receptors by endogenous acetylcholine were observed under stimulation of mass optic fibers. This study was designed to determine whether endogenous acetylcholine facilitates frog retinotectal transmission, provided only the synapses of an individual optic axon are activated, and to evaluate the feasible extent of nicotinic facilitation in these synapses by applied agonist. To this end, the effects of cholinergic drugs on the extracellular action and synaptic potentials recorded from the terminal arborization of a separate retinotectal fiber (in layer F of the tectum) were investigated in vivo. Glutamatergic nature of retinotectal synapses was reexamined by treatment with kynurenic acid. Both kynurenic acid (0.25–1 mM) and d-tubocurarine chloride (10–15 μM) significantly depressed the synaptic potentials. Carbamylcholine chloride (50–150 μM) evoked a large augmentation of the synaptic potentials and a slight but statistically significant decrease of the action potentials. D-tubocurarine reduced the effect of carbamylcholine. Pilocarpine hydrochloride (50 μM) had only a weak effect. The paired-pulse facilitation of the synaptic potentials changed significantly under the action of carbamylcholine and d-tubocurarine. The obtained results suggest that the glutamate release from activated synapses of individual retinotectal axons is facilitated by endogenous acetylcholine via presynaptic nicotinic receptors. Under used stimulation conditions, this modulation mechanism was employed only partially since its activation by applied carbamylcholine could enhance synaptic transmission up to 2.8 times.

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Increased quinolinic acid metabolism following neuronal degeneration in the rat hippocampus

Brain Research ◽

10.1016/0006-8993(87)91551-4 ◽

1987 ◽

Vol 436 (1) ◽

pp. 18-24 ◽

Cited By ~ 27

Author(s):

Carmela Speciale ◽

Etsuo Okuno ◽

Robert Schwarcz

Keyword(s):

Quinolinic Acid ◽

Acid Metabolism ◽

Neuronal Degeneration ◽

Rat Hippocampus

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Responses of Deep Entorhinal Cortex are Epileptiform in an Electrogenic Rat Model of Chronic Temporal Lobe Epilepsy

Journal of Neurophysiology ◽

10.1152/jn.1998.80.1.230 ◽

1998 ◽

Vol 80 (1) ◽

pp. 230-240 ◽

Cited By ~ 33

Author(s):

Nathan B. Fountain ◽

Jonathan Bear ◽

Edward H. Bertram ◽

Eric W. Lothman

Keyword(s):

Temporal Lobe Epilepsy ◽

Entorhinal Cortex ◽

Temporal Lobe ◽

Rat Model ◽

Action Potentials ◽

Nmda Antagonist ◽

Target Cells ◽

Excitatory Postsynaptic Potential ◽

Inhibitory Interneurons ◽

And Control

Fountain, Nathan B., Jonathan Bear, Edward H. Bertram III, and Eric W. Lothman. Responses of deep entorhinal cortex are epileptiform in an electrogenic rat model of chronic temporal lobe epilepsy. J. Neurophysiol. 80: 230–240, 1998. We investigated whether entorhinal cortex (EC) layer IV neurons are hyperexcitable in the post-selfsustaining limbic status epilepticus (post-SSLSE) animal model of temporal lobe epilepsy. We studied naive rats ( n = 44), epileptic rats that had experienced SSLSE resulting in spontaneous seizures ( n = 45), and electrode controls ( n = 7). There were no differences between electrode control and naive groups, which were pooled into a single control group. Intracellular and extracellular recordings were made from deep layers of EC, targeting layer IV, which was activated by stimulation of the superficial layers of EC or the angular bundle. There were no differences between epileptic and control neurons in basic cellular characteristics, and all neurons were quiescent under resting conditions. In control tissue, 77% of evoked intracellular responses consisted of a short-duration [8.6 ± 1.3 (SE) ms] excitatory postsynaptic potential and a single action potential followed by γ-aminobutyric acid-A (GABAA) and GABAB inhibitory post synaptic potentials (IPSPs). Ten percent of controls did not contain IPSPs. In chronically epileptic tissue, evoked intracellular responses demonstrated prolonged depolarizing potentials (256 ± 39 ms), multiple action potentials (13 ± 4), and no IPSPs. Ten percent of epileptic responses were followed by rhythmic “clonic” depolarizations. Epileptic responses exhibited an all-or-none response to progressive increases in stimulus intensity and required less stimulation to elicit action potentials. In both epileptic and control animals, intracellular responses correlated precisely in morphology and duration with extracellular field potentials. Severing the hippocampus from the EC did not alter the responses. Duration of intracellular epileptic responses was reduced 22% by the N-methyl-d-aspartate (NMDA) antagonist d(−)-2-amino-5-phosphonovaleric acid (APV), but they did not return to normal and IPSPs were not restored. Epileptic and control responses were abolished by the non-NMDA antagonist 6,7-dinitroquinoxaline-2-3-dione (DNQX). A monosynaptic IPSP protocol was used to test connectivity of inhibitory interneurons to primary cells by direct activation of interneurons with a stimulating electrode placed near the recording electrode in the presence of APV and DNQX. Using this protocol, IPSPs similar to control ( P > 0.05) were seen in epileptic cells. The findings demonstrate that deep layer EC cells are hyperexcitable or “epileptiform” in this model. Hyperexcitability is not due to interactions with the hippocampus. It is due partially to augmented NMDA-mediated excitation. The lack of IPSPs in epileptic neurons may suggest inhibition is impaired, but we found evidence that inhibitory interneurons are connected to their target cells and are capable of inducing IPSPs.

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Synaptic inputs and action potentials of magnocellular neuropeptidergic cells: Intracellular recording and staining in slices of rat hypothalamus

Brain Research Bulletin ◽

10.1016/0361-9230(82)90031-4 ◽

1982 ◽

Vol 8 (1) ◽

pp. 87-93 ◽

Cited By ~ 12

Author(s):

Brian A. MacVicar ◽

R.David Andrew ◽

F.Edward Dudek ◽

Glenn I. Hatton

Keyword(s):

Intracellular Recording ◽

Action Potentials ◽

Synaptic Inputs ◽

Rat Hypothalamus

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Functional implications of burst firing and single spike activity in lateral geniculate relay neurons

Neuroscience ◽

10.1016/0306-4522(90)90225-s ◽

1990 ◽

Vol 39 (1) ◽

pp. 103-113 ◽

Cited By ~ 201

Author(s):

D.A. McCormick ◽

H.R. Feeser

Keyword(s):

Spike Activity ◽

Burst Firing ◽

Lateral Geniculate ◽

Functional Implications ◽

Single Spike ◽

Relay Neurons

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Nocturnal Gamma-Hydroxybutyrate Reduces Cortisol-Awakening Response and Morning Kynurenine Pathway Metabolites in Healthy Volunteers

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz047 ◽

2019 ◽

Vol 22 (10) ◽

pp. 631-639

Author(s):

D A Dornbierer ◽

M Boxler ◽

C D Voegel ◽

B Stucky ◽

A E Steuer ◽

...

Keyword(s):

Quinolinic Acid ◽

Kynurenic Acid ◽

Killer Cell ◽

Affective State ◽

Neuropsychiatric Disorders ◽

Cortisol Awakening Response ◽

Therapeutic Effects ◽

Cell Counts ◽

Acid Ratio ◽

Gamma Hydroxybutyrate

Abstract Background Gamma-hydroxybutyrate (GHB; or sodium oxybate) is an endogenous GHB-/gamma-aminobutyric acid B receptor agonist. It is approved for application in narcolepsy and has been proposed for the potential treatment of Alzheimer’s disease, Parkinson’s disease, fibromyalgia, and depression, all of which involve neuro-immunological processes. Tryptophan catabolites (TRYCATs), the cortisol-awakening response (CAR), and brain-derived neurotrophic factor (BDNF) have been suggested as peripheral biomarkers of neuropsychiatric disorders. GHB has been shown to induce a delayed reduction of T helper and natural killer cell counts and alter basal cortisol levels, but GHB’s effects on TRYCATs, CAR, and BDNF are unknown. Methods Therefore, TRYCAT and BDNF serum levels, as well as CAR and the affective state (Positive and Negative Affect Schedule [PANAS]) were measured in the morning after a single nocturnal dose of GHB (50 mg/kg body weight) in 20 healthy male volunteers in a placebo-controlled, balanced, randomized, double-blind, cross-over design. Results In the morning after nocturnal GHB administration, the TRYCATs indolelactic acid, kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid; the 3-hydroxykynurenine to kynurenic acid ratio; and the CAR were significantly reduced (P < 0.05–0.001, Benjamini-Hochberg corrected). The quinolinic acid to kynurenic acid ratio was reduced by trend. Serotonin, tryptophan, and BDNF levels, as well as PANAS scores in the morning, remained unchanged after a nocturnal GHB challenge. Conclusions GHB has post-acute effects on peripheral biomarkers of neuropsychiatric disorders, which might be a model to explain some of its therapeutic effects in disorders involving neuro-immunological pathologies. This study was registered at ClinicalTrials.gov as NCT02342366.

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Activation of Metabotropic Glutamate 2/3 Receptors Reverses the Effects of NMDA Receptor Hypofunction on Prefrontal Cortex Unit Activity in Awake Rats

Journal of Neurophysiology ◽

10.1152/jn.00875.2004 ◽

2005 ◽

Vol 93 (4) ◽

pp. 1989-2001 ◽

Cited By ~ 105

Author(s):

Houman Homayoun ◽

Mark E. Jackson ◽

Bita Moghaddam

Keyword(s):

Prefrontal Cortex ◽

Nmda Receptor ◽

Firing Rate ◽

Spike Activity ◽

Systemic Exposure ◽

Nmda Antagonist ◽

Laboratory Animals ◽

Cellular Mechanisms ◽

Physiological Basis ◽

Metabotropic Glutamate

Systemic exposure to N-methyl-d-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)–dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.

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