GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine

A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior.

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In vivo patch-clamp analysis of the actions of 5-HT on excitatory synaptic transmission evoked in rat substantia gelatinosa neurons by cutaneous mechanical stimuli

Neuroscience Research ◽

10.1016/s0168-0102(00)81385-1 ◽

2000 ◽

Vol 38 ◽

pp. S90

Author(s):

H Furue

Keyword(s):

Patch Clamp ◽

Synaptic Transmission ◽

Excitatory Synaptic Transmission ◽

Substantia Gelatinosa ◽

Mechanical Stimuli

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GABAA Receptor–Mediated Miniature Postsynaptic Currents and α-Subunit Expression in Developing Cortical Neurons

Journal of Neurophysiology ◽

10.1152/jn.1999.82.6.3286 ◽

1999 ◽

Vol 82 (6) ◽

pp. 3286-3297 ◽

Cited By ~ 80

Author(s):

D. D. Dunning ◽

C. L. Hoover ◽

I. Soltesz ◽

M. A. Smith ◽

D. K. O'Dowd

Keyword(s):

Synaptic Transmission ◽

Decay Time ◽

Cortical Neurons ◽

Pcr Analysis ◽

Decay Kinetics ◽

Newborn Mice ◽

Α Subunit ◽

Postsynaptic Currents ◽

Subunit Expression

Previous studies have described maturational changes in GABAergic inhibitory synaptic transmission in the rodent somatosensory cortex during the early postnatal period. To determine whether alterations in the functional properties of synaptically localized GABAAreceptors (GABAARs) contribute to development of inhibitory transmission, we used the whole cell recording technique to examine GABAergic miniature postsynaptic currents (mPSCs) in developing cortical neurons. Neurons harvested from somatosensory cortices of newborn mice showed a progressive, eightfold increase in GABAergic mPSC frequency during the first 4 wk of development in dissociated cell culture. A twofold decrease in the decay time of the GABAergic mPSCs, between 1 and 4 wk, demonstrates a functional change in the properties of GABAARs mediating synaptic transmission in cortical neurons during development in culture. A similar maturational profile observed in GABAergic mPSC frequency and decay time in cortical neurons developing in vivo (assessed in slices), suggests that these changes in synaptically localized GABAARs contribute to development of inhibition in the rodent neocortex. Pharmacological and reverse transcription-polymerase chain reaction (RT-PCR) studies were conducted to determine whether changes in subunit expression might contribute to the observed developmental alterations in synaptic GABAARs. Zolpidem (300 nM), a subunit-selective benzodiazepine agonist with high affinity for α1-subunits, caused a reversible slowing of the mPSC decay kinetics in cultured cortical neurons. Development was characterized by an increase in the potency of zolpidem in modulating the mPSC decay, suggesting a maturational increase in percentage of functionally active GABAARs containing α1 subunits. The relative expression of α1 versus α5 GABAAR subunit mRNA in cortical tissue, both in vivo and in vitro, also increased during this same period. Furthermore, single-cell RT-multiplex PCR analysis revealed more rapidly decaying mPSCs in individual neurons in which α1 versus α5 mRNA was amplified. Together these data suggest that changes in α-subunit composition of GABAARs contribute to the maturation of GABAergic mPSCs mediating inhibition in developing cortical neurons.

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Substance P Depresses Excitatory Synaptic Transmission in the Nucleus Accumbens Through Dopaminergic and Purinergic Mechanisms

Journal of Neurophysiology ◽

10.1152/jn.00854.2002 ◽

2003 ◽

Vol 89 (2) ◽

pp. 728-737 ◽

Cited By ~ 25

Author(s):

Samuel B. Kombian ◽

Kethireddy V. V. Ananthalakshmi ◽

Subramanian S. Parvathy ◽

Wandikayi C. Matowe

Keyword(s):

Nucleus Accumbens ◽

Substance P ◽

Synaptic Transmission ◽

Input Resistance ◽

Nmda Receptor Antagonist ◽

Excitatory Synaptic Transmission ◽

Nk1 Receptor ◽

Dose Dependent Decrease ◽

Neurokinin 1 ◽

Synaptic Effects

Substance P (SP) is an undecapeptide that is co-localized with conventional transmitters in the nucleus accumbens (NAc). Its neurochemical and behavioral effects resemble those of cocaine and amphetamine. How SP accomplishes these effects is not known, partly because its cellular and synaptic effects are not well characterized. Using whole cell and nystatin-perforated patch recording in rat forebrain slices, we show here that SP, an excitatory neuropeptide, depresses evoked excitatory postsynaptic currents (EPSCs) and potentials (EPSPs) in NAc through intermediate neuromodulators. SP caused a partially reversible, dose-dependent decrease in evoked EPSCs. This effect was mimicked by a neurokinin-1 (NK1) receptor-selective agonist, [Sar9, Met (O2)11]-SP and blocked by a NK1 receptor-selective antagonist, L 732 138. Both the SP- and [Sar9, Met (O2)11]-SP-induced synaptic depressions were accompanied by increases in paired pulse ratio (PPR), effects that were also blocked by L 732 138. In contrast to its effect on PPR, SP did not produce significant changes in the holding current, input resistance, EPSC decay rate (τ), and steady-state I-V curves of the recorded cells. The SP-induced synaptic depressions were prevented by dopamine receptor blockade using SCH23390 and haloperidol, but not by sulpiride. In addition, the SP-induced synaptic depression was blocked by an adenosine A1 receptor blocker 8-cyclopentyltheophylline (8-CPT) but not the N-methyl-d-aspartate (NMDA) receptor antagonist d-APV. These data show that SP, by activating presynaptic NK1 receptors, depresses excitatory synaptic transmission indirectly by enhancing extracellular dopamine and adenosine levels. Since the cellular and synaptic effects of SP resemble those of cocaine and amphetamine, it may serve as an endogenous psychogenic peptide.

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The Delta-Opioid Receptor Agonist D-Ala2-D-Leu2-Enkephalin Enhances Hypoxic Depression of Excitatory Synaptic Transmission and Improves Recovery of Rat Cortical Neurons from Hypoxia in vitro

Pharmacology ◽

10.1159/000449468 ◽

2016 ◽

Vol 99 (1-2) ◽

pp. 9-18 ◽

Cited By ~ 2

Author(s):

Andreas Merkenschlager ◽

Marcus Bloßfeld ◽

Karen Nieber

Keyword(s):

Synaptic Transmission ◽

Opioid Receptor ◽

Cortical Neurons ◽

Receptor Agonist ◽

Excitatory Synaptic Transmission ◽

Delta Opioid Receptor ◽

Opioid Receptor Agonist ◽

Rat Cortical Neurons

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Suppression of excitatory synaptic transmission can facilitate low-calcium epileptiform activity in the hippocampus in vivo

Brain Research ◽

10.1016/j.brainres.2004.09.063 ◽

2004 ◽

Vol 1030 (1) ◽

pp. 57-65 ◽

Cited By ~ 8

Author(s):

Zhouyan Feng ◽

Dominique M. Durand

Keyword(s):

Synaptic Transmission ◽

Epileptiform Activity ◽

Excitatory Synaptic Transmission ◽

Low Calcium

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Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse

10.1101/2020.10.23.352120 ◽

2020 ◽

Author(s):

Timothy S. Balmer ◽

Carolina Borges-Merjane ◽

Laurence O. Trussell

Keyword(s):

Synaptic Transmission ◽

Mossy Fiber ◽

Synaptic Cleft ◽

Synaptic Activity ◽

Brush Cells ◽

Incomplete Removal ◽

Unipolar Brush Cells ◽

Ambient Glutamate ◽

Synaptic Responses

AbstractSynapses of glutamatergic mossy fiber onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC’s large dendritic brush. Using brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBC. The source of ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Changing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.

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Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse

eLife ◽

10.7554/elife.63819 ◽

2021 ◽

Vol 10 ◽

Author(s):

Timothy S Balmer ◽

Carolina Borges-Merjane ◽

Laurence O Trussell

Keyword(s):

Synaptic Transmission ◽

Mossy Fiber ◽

Mossy Fibers ◽

Synaptic Cleft ◽

Synaptic Activity ◽

Brush Cells ◽

Incomplete Removal ◽

Unipolar Brush Cells ◽

Ambient Glutamate

Synapses of glutamatergic mossy fibers onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC's large dendritic brush. Using mouse brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBCs. The source of this ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Increasing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.

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