Brief Trains of Action Potentials Enhance Pyramidal Neuron Excitability Via Endocannabinoid-Mediated Suppression of Inhibition

2004 ◽  
Vol 92 (4) ◽  
pp. 2105-2112 ◽  
Author(s):  
Dale A. Fortin ◽  
Joseph Trettel ◽  
Eric S. Levine
Keyword(s):  
Action Potentials ◽  
Time Course ◽  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Afferent Inhibition ◽  
Transport Inhibitor ◽  
Gabaergic Synapses ◽  
The Impact ◽  
Somatic Inhibition

Depolarization-induced suppression of inhibition (DSI) is a form of retrograde signaling at GABAergic synapses that is initiated by the calcium- and depolarization-dependent release of endocannabinoids from postsynaptic neurons. In the neocortex, pyramidal neurons (PNs) appear to use DSI as a mechanism for regulating somatic inhibition from a subpopulation of GABAergic inputs that express the type 1 cannabinoid receptor. Although postsynaptic control of afferent inhibition may directly influence the integrative properties of neocortical PNs, little is known about the patterns of activity that evoke endocannabinoid release and the impact such disinhibition may have on the excitability of PNs. Here we provide the first systematic survey of action potential (AP)-induced DSI in the neocortex. The magnitude and time course of DSI was directly related to the number and frequency of postsynaptic APs with significant suppression induced by a 20-Hz train containing as few as three APs. This AP-induced DSI was mediated by endocannabinoids as it was prevented by the cannabinoid receptor antagonist AM251 and potentiated by the endocannabinoid transport inhibitor AM404. We also explored the effects of endocannabinoid-mediated DSI on PN excitability. We found that single AP trains markedly increased PN responsiveness to excitatory synaptic inputs and promoted AP discharge by suppressing GABAergic inhibition. The time course of this effect paralleled DSI expression and was completely blocked by AM251. Taken together, our data suggest a role for endocannabinoids in regulating the output of cortical PNs.

Lack of Depolarization-Induced Suppression of Inhibition (DSI) in Layer 2/3 Interneurons That Receive Cannabinoid-Sensitive Inhibitory Inputs

2007 ◽  
Vol 98 (5) ◽  
pp. 2517-2524 ◽  
Author(s):  
Fouad Lemtiri-Chlieh ◽  
Eric S. Levine
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Brain Slices ◽  
Gaba Release ◽  
Synaptic Activity ◽  
Layer 2 ◽  
Fast Spiking ◽  
Whole Cell Recordings

In layer 2/3 of neocortex, brief trains of action potentials in pyramidal neurons (PNs) induce the mobilization of endogenous cannabinoids (eCBs), resulting in a depression of GABA release from the terminals of inhibitory interneurons (INs). This depolarization-induced suppression of inhibition (DSI) is mediated by activation of the type 1 cannabinoid receptor (CB1) on presynaptic terminals of a subset of INs. However, it is not clear whether CB1 receptors are also expressed at synapses between INs, and whether INs can release eCBs in response to depolarization. In the present studies, brain slices containing somatosensory cortex were prepared from 14- to 21-day-old CD-1 mice. Whole cell recordings were obtained from layer 2/3 PNs and from INs classified as regular spiking nonpyramidal, irregular spiking, or fast spiking. For all three classes of INs, the cannabinoid agonist WIN55,212-2 suppressed inhibitory synaptic activity, similar to the effect seen in PNs. In addition, trains of action potentials in PNs resulted in significant DSI. In INs, however, DSI was not seen in any cell type, even with prolonged high-frequency spike trains that produced calcium increases comparable to that seen with DSI induction in PNs. In addition, blocking eCB reuptake with AM404, which enhanced DSI in PNs, failed to unmask any DSI in INs. Thus the lack of DSI in INs does not appear to be due to an insufficient increase in intracellular calcium or enhanced reuptake. These results suggest that layer 2/3 INs receive CB1-expressing inhibitory inputs, but that eCBs are not released by these INs.

Endocannabinoids Mediate Rapid Retrograde Signaling At Interneuron → Pyramidal Neuron Synapses of the Neocortex

2003 ◽  
Vol 89 (4) ◽  
pp. 2334-2338 ◽  
Author(s):  
Joseph Trettel ◽  
Eric S. Levine
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Gaba Release ◽  
Inhibitory Interneurons ◽  
Strongly Correlated ◽  
Inhibitory Strength ◽  
Activity Dependent ◽  
Whole Cell Recordings

In the neocortex, inhibitory interneurons tightly regulate the firing patterns and integrative properties of pyramidal neurons (PNs). The endocannabinoid system of the neocortex may play an important role in the activity-dependent regulation of inhibitory (i.e., GABAergic) inputs received by PNs. In the present study, using whole cell recordings from layer 2/3 PNs in slices of mouse sensory cortex, we have identified a role for PN-derived endocannabinoids in the control of afferent inhibitory strength. Pairing evoked inhibitory currents with repeated epochs of postsynaptic depolarization led to a transient suppression of inhibition that was induced by a rise in postsynaptic Ca2+ and was expressed as a reduction in presynaptic GABA release. An antagonist (AM251) of the type-1 cannabinoid receptor blocked the depolarization-induced suppression of evoked inhibitory postsynaptic currents (eIPSCs), and the cannabinoid WIN55,212-2 reduced eIPSC amplitude and occluded suppression. The degree of WIN55,212-2-mediated inhibition of eIPSCs was strongly correlated with the magnitude of depolarization-induced suppression of the eIPSCs, suggesting that the WIN-sensitive afferents are suppressed by PN depolarization. Moreover, blocking endocannabinoid uptake with AM404 strongly modulated the kinetics and magnitude of eIPSC suppression. We conclude that the release of endocannabinoids from PNs allows for the postsynaptic control of presynaptic inhibition and could have profound consequences for the integrative properties of neocortical PNs.

scholarly journals Psychosocial Stress and Cannabinoid Drugs Affect Acetylation of α-tubulin (K40) and Gene Expression in the Prefrontal Cortex of Adult Mice

2021 ◽  
Author(s):  
Jordi Tomas-Roig ◽  
Shyam Sundar Ramasamy ◽  
Diana Zbarsky ◽  
Ursula Havemann-Reinecke ◽  
Sigrid Hoyer-Fender
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Psychosocial Stress ◽  
Cannabinoid Receptor ◽  
Brain Plasticity ◽  
Receptor Type ◽  
Tubulin Acetylation ◽  
Cannabinoid Receptor Type 1 ◽  
The Impact

Abstract The dynamics of neuronal microtubules are essential for brain plasticity. Vesicular transport and synaptic transmission, additionally, requires acetylation of α-tubulin, and aberrant tubulin acetylation and neurobiological deficits are associated. Prolonged exposure to a stressor or consumption of drugs of abuse, like marihuana, lead to neurological changes and psychotic disorders. Here, we studied the effect of psychosocial stress and the administration of cannabinoid receptor type 1 drugs on α-tubulin acetylation in different brain regions of mice. We found significantly decreased tubulin acetylation in the prefrontal cortex and the dorsal striatum in stressed mice. The impact of cannabinoid drugs on stress-induced microtubule disturbance was investigated by administration of the cannabinoid receptor agonist WIN55,212-2 and/or antagonist rimonabant. In both, control and stressed mice, the administration of WIN55,212-2 significantly increased the tubulin acetylation in the prefrontal cortex whereas administration of both cannabinoid drugs acted antagonistically indicating a cannabinoid receptor type 1 mediated effect. The analysis of gene expression in the prefrontal cortex showed a consistent expression of ApoE attributable to either psychosocial stress or administration of the cannabinoid agonist. Additionally, ApoE expression inversely correlated with acetylated tubulin levels when comparing controls and stressed mice treated with WIN55,212-2 whereas rimonabant treatment showed the opposite.

scholarly journals DM1 Transgenic Mice Exhibit Abnormal Neurotransmitter Homeostasis and Synaptic Plasticity in Association with RNA Foci and Mis-Splicing in the Hippocampus

2022 ◽  
Vol 23 (2) ◽  
pp. 592
Author(s):  
Brigitte Potier ◽  
Louison Lallemant ◽  
Sandrine Parrot ◽  
Aline Huguet-Lachon ◽  
Geneviève Gourdon ◽  
...  
Keyword(s):  
Time Course ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
Glutamate Uptake ◽  
Hippocampal Slices ◽  
Synaptic Cleft ◽  
Synaptic Dysfunction ◽  
Functional Changes ◽  
Rna Foci ◽  
The Impact

Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disease mediated by a toxic gain of function of mutant RNAs. The neuropsychological manifestations affect multiple domains of cognition and behavior, but their etiology remains elusive. Transgenic DMSXL mice carry the DM1 mutation, show behavioral abnormalities, and express low levels of GLT1, a critical regulator of glutamate concentration in the synaptic cleft. However, the impact of glutamate homeostasis on neurotransmission in DM1 remains unknown. We confirmed reduced glutamate uptake in the DMSXL hippocampus. Patch clamp recordings in hippocampal slices revealed increased amplitude of tonic glutamate currents in DMSXL CA1 pyramidal neurons and DG granule cells, likely mediated by higher levels of ambient glutamate. Unexpectedly, extracellular GABA levels and tonic current were also elevated in DMSXL mice. Finally, we found evidence of synaptic dysfunction in DMSXL mice, suggestive of abnormal short-term plasticity, illustrated by an altered LTP time course in DG and in CA1. Synaptic dysfunction was accompanied by RNA foci accumulation in localized areas of the hippocampus and by the mis-splicing of candidate genes with relevant functions in neurotransmission. Molecular and functional changes triggered by toxic RNA may induce synaptic abnormalities in restricted brain areas that favor neuronal dysfunction.

scholarly journals NPAS4 recruits CCK basket cell synapses and enhances cannabinoid-sensitive inhibition in the mouse hippocampus

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Andrea L Hartzell ◽  
Kelly M Martyniuk ◽  
G Stefano Brigidi ◽  
Daniel A Heinz ◽  
Nathalie A Djaja ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Sensory Experience ◽  
Early Gene ◽  
Dependent Manner ◽  
Important Regulator ◽  
And Function ◽  
The Impact ◽  
Somatic Inhibition ◽  
Inhibitory Synaptic Input ◽  
Major Target

Experience-dependent expression of immediate-early gene transcription factors (IEG-TFs) can transiently change the transcriptome of active neurons and initiate persistent changes in cellular function. However, the impact of IEG-TFs on circuit connectivity and function is poorly understood. We investigate the specificity with which the IEG-TF NPAS4 governs experience-dependent changes in inhibitory synaptic input onto CA1 pyramidal neurons (PNs). We show that novel sensory experience selectively enhances somatic inhibition mediated by cholecystokinin-expressing basket cells (CCKBCs) in an NPAS4-dependent manner. NPAS4 specifically increases the number of synapses made onto PNs by individual CCKBCs without altering synaptic properties. Additionally, we find that sensory experience-driven NPAS4 expression enhances depolarization-induced suppression of inhibition (DSI), a short-term form of cannabinoid-mediated plasticity expressed at CCKBC synapses. Our results indicate that CCKBC inputs are a major target of the NPAS4-dependent transcriptional program in PNs and that NPAS4 is an important regulator of plasticity mediated by endogenous cannabinoids.

scholarly journals Time-course Profiling of Bovine Herpesvirus Type 1 and Host Cell Transcriptomes using Multiplatform Sequencing

2020 ◽  
Author(s):  
Norbert Moldován ◽  
Zoltán Maróti ◽  
Gábor Torma ◽  
Gábor Gulyás ◽  
Ákos Hornyák ◽  
...  
Keyword(s):  
Host Cell ◽  
Time Course ◽  
Splice Variants ◽  
Bovine Herpesvirus ◽  
Viral Mrnas ◽  
Herpesvirus Type ◽  
Long Read ◽  
Bovine Herpesvirus Type 1 ◽  
The Impact

SUMMARYLong-read sequencing (LRS) has become a standard approach for transcriptome analysis in recent years. This technology is also used for the identification and annotation of genes of various organisms, including viruses. Bovine herpesvirus type 1 (BoHV-1) is an important pathogen of cattle worldwide. However, the transcriptome of this virus is still largely unannotated. This study reports the profiling of the dynamic lytic transcriptome of BoHV-1 using two long-read sequencing (LRS) techniques, the Oxford Nanopore Technology (ONT) MinION, and the Illumina LoopSeq synthetic LRS methods, using multiple library preparation protocols. In this work, we annotated viral mRNAs and non-coding transcripts, and a large number of transcript isoforms, including transcription start and end sites, as well as splice variants of BoHV-1. Very long polycistronic and complex viral transcripts were also detected. Our analysis demonstrated an extremely complex pattern of transcriptional overlaps formed by transcriptional read-throughs or overlapping the 5’-untranslated regions of divergently-oriented transcripts. The impact of the viral infection on the host cell transcriptome was also assessed. Our results demonstrate that genes associated with antiviral response as well as viral transcription and translation are upregulated.

Layer-Specific Generation and Propagation of Seizures in Slices of Developing Neocortex: Role of Excitatory GABAergic Synapses

2008 ◽  
Vol 100 (2) ◽  
pp. 620-628 ◽  
Author(s):  
Sylvain Rheims ◽  
Alfonso Represa ◽  
Yehezkel Ben-Ari ◽  
Yuri Zilberter
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Neonatal Period ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Nmda Channel ◽  
Gabaergic Synapses ◽  
Developing Neocortex ◽  
Excitatory Gaba

The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6–P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential ( Em), we show that transition from IISs to ISs is associated with a gradual Em depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by Em depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

scholarly journals Cannabinoids Depress Inhibitory Synaptic Inputs Received by Layer 2/3 Pyramidal Neurons of the Neocortex

2002 ◽  
Vol 88 (1) ◽  
pp. 534-539 ◽  
Author(s):  
Joseph Trettel ◽  
Eric S. Levine
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Cell Voltage ◽  
Gaba Release ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Presynaptic Site ◽  
Layer 2 ◽  
Kinetics Of

Using whole cell voltage-clamp recordings we investigated the effects of a synthetic cannabinoid (WIN55,212-2) on inhibitory inputs received by layer 2/3 pyramidal neurons in slices of the mouse auditory cortex. Activation of the type 1 cannabinoid receptor (CB1R) with WIN55,212-2 reliably reduced the amplitude of GABAergic inhibitory postsynaptic currents evoked by extracellular stimulation within layer 2/3. The suppression of this inhibition was blocked and reversed by the highly selective CB1R antagonist AM251, confirming a CB1R-mediated inhibition. Pairing evoked inhibitory postsynaptic currents (IPSCs) at short interstimulus intervals while applying WIN55,212-2 resulted in an increase in paired-pulse facilitation suggesting that the probability of GABA release was reduced. A presynaptic site of cannabinoid action was verified by an observed decrease in the frequency with no change in the amplitude or kinetics of action potential–independent postsynaptic currents (mIPSCs). When Cd2+ was added or Ca2+ was omitted from the recording solution, the remaining fraction of Ca2+-independent mIPSCs did not respond to WIN55,212-2. These data suggest that cannabinoids are capable of suppressing the inhibition of neocortical pyramidal neurons by depressing Ca2+-dependent GABA release from local interneurons.

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