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1.
Proc Natl Acad Sci U S A ; 112(2): E204-13, 2015 Jan 13.
Article in English | MEDLINE | ID: mdl-25550512

ABSTRACT

NMDA receptors (NMDARs) require the coagonists D-serine or glycine for their activation, but whether the identity of the coagonist could be synapse specific and developmentally regulated remains elusive. We therefore investigated the contribution of D-serine and glycine by recording NMDAR-mediated responses at hippocampal Schaffer collaterals (SC)-CA1 and medial perforant path-dentate gyrus (mPP-DG) synapses in juvenile and adult rats. Selective depletion of endogenous coagonists with enzymatic scavengers as well as pharmacological inhibition of endogenous D-amino acid oxidase activity revealed that D-serine is the preferred coagonist at SC-CA1 mature synapses, whereas, unexpectedly, glycine is mainly involved at mPP-DG synapses. Nevertheless, both coagonist functions are driven by the levels of synaptic activity as inferred by recording long-term potentiation generated at both connections. This regional compartmentalization in the coagonist identity is associated to different GluN1/GluN2A to GluN1/GluN2B subunit composition of synaptic NMDARs. During postnatal development, the replacement of GluN2B- by GluN2A-containing NMDARs at SC-CA1 synapses parallels a change in the identity of the coagonist from glycine to D-serine. In contrast, NMDARs subunit composition at mPP-DG synapses is not altered and glycine remains the main coagonist throughout postnatal development. Altogether, our observations disclose an unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of D-serine And Glycine In Modulating Nmdars During The Maturation Of Tripartite Glutamatergic Synapses.


Subject(s)
Hippocampus/growth & development , Hippocampus/metabolism , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/metabolism , Synapses/metabolism , Animals , Animals, Newborn , Astrocytes/metabolism , CA1 Region, Hippocampal/growth & development , CA1 Region, Hippocampal/metabolism , Dentate Gyrus/growth & development , Dentate Gyrus/metabolism , Glycine/metabolism , Long-Term Potentiation , Male , Neurons/metabolism , Rats , Serine/metabolism
2.
Cereb Cortex ; 25(9): 2440-55, 2015 Sep.
Article in English | MEDLINE | ID: mdl-24646614

ABSTRACT

Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition.


Subject(s)
Cannabinoids/metabolism , Inhibitory Postsynaptic Potentials/physiology , Neural Inhibition/physiology , Receptors, GABA/metabolism , Action Potentials/drug effects , Action Potentials/genetics , Animals , Animals, Newborn , Cannabinoids/pharmacology , GABA Agents/pharmacology , Hippocampus/cytology , Humans , In Vitro Techniques , Inhibitory Postsynaptic Potentials/drug effects , Inhibitory Postsynaptic Potentials/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Inhibition/drug effects , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB1/metabolism , Synaptic Transmission/drug effects , Synaptic Transmission/genetics , Transfection
3.
J Neurosci ; 25(33): 7499-506, 2005 Aug 17.
Article in English | MEDLINE | ID: mdl-16107637

ABSTRACT

At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabinoid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR) channels. In isolated hippocampal pyramidal and Purkinje cerebellar neurons, endogenous cannabinoids anandamide and 2-arachidonylglycerol, applied at physiological concentrations, inhibited the amplitude and altered the kinetics of rise time, desensitization, and deactivation of the glycine-activated current (I(Gly)) in a concentration-dependent manner. These effects of cannabinoids were observed in the presence of cannabinoid CB1/CB3, vanilloid receptor 1 antagonists, and the G-protein inhibitor GDPbetaS, suggesting a direct action of cannabinoids on GlyRs. The effect of cannabinoids on I(Gly) desensitization was strongly voltage dependent. We also demonstrate that, in the presence of a GABA(A) receptor antagonist, GlyRs may contribute to the generation of seizure-like activity induced by short bursts (seven stimuli) of high-frequency stimulation of inputs to hippocampal CA1 region, because this activity was diminished by selective GlyR antagonists (strychnine and ginkgolides B and J). The GlyR-mediated rhythmic activity was also reduced by cannabinoids (anandamide) in the presence of a CB1 receptor antagonist. These results suggest that the direct inhibition of GlyRs by endocannabinoids can modulate the hippocampal network activity.


Subject(s)
Cannabinoid Receptor Modulators/physiology , Neural Inhibition/physiology , Neurons/drug effects , Neurons/physiology , Receptors, Glycine/agonists , Receptors, Glycine/physiology , Animals , Cannabinoid Receptor Agonists , Central Nervous System/drug effects , Central Nervous System/physiology , Dose-Response Relationship, Drug , In Vitro Techniques , Rats , Rats, Wistar , Receptors, Cannabinoid/physiology
4.
J Physiol ; 556(Pt 1): 121-34, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-14742725

ABSTRACT

N-type voltage-dependent Ca(2+) channels (N-VDCCs) play important roles in neurotransmitter release and certain postsynaptic phenomena. These channels are modulated by a number of intracellular factors, notably by Gbetagamma subunits of G proteins, which inhibit N-VDCCs in a voltage-dependent (VD) manner. Here we show that an increase in intracellular Na(+) concentration inhibits N-VDCCs in hippocampal pyramidal neurones and in Xenopus oocytes. In acutely dissociated hippocampal neurones, Ba(2+) current via N-VDCCs was inhibited by Na(+) influx caused by the activation of NMDA receptor channels. In Xenopus oocytes expressing N-VDCCs, Ba(2+) currents were inhibited by Na(+) influx and enhanced by depletion of Na(+), after incubation in a Na(+)-free extracellular solution. The Na(+)-induced inhibition was accompanied by the development of VD facilitation, a hallmark of a Gbetagamma-dependent process. Na(+)-induced regulation of N-VDCCs is Gbetagamma dependent, as suggested by the blocking of Na(+) effects by Gbetagamma scavengers and by excess Gbetagamma, and may be mediated by the Na(+)-induced dissociation of Galphabetagamma heterotrimers. N-VDCCs may be novel effectors of Na(+)ion, regulated by the Na(+) concentration via Gbetagamma.


Subject(s)
Calcium Channels, N-Type/metabolism , GTP-Binding Protein beta Subunits/physiology , GTP-Binding Protein gamma Subunits/physiology , Intracellular Fluid/metabolism , Sodium/metabolism , Animals , Calcium Channels, N-Type/physiology , Electrophysiology , Female , GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , GTP-Binding Protein beta Subunits/antagonists & inhibitors , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/antagonists & inhibitors , GTP-Binding Protein gamma Subunits/metabolism , Hippocampus/cytology , Hippocampus/metabolism , In Vitro Techniques , Neurotransmitter Agents/metabolism , Oocytes , Pyramidal Cells/metabolism , Rats , Rats, Wistar , Xenopus laevis
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