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 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.

Dichotomy of Action-Potential Backpropagation in CA1 Pyramidal Neuron Dendrites

2001 ◽  
Vol 86 (6) ◽  
pp. 2998-3010 ◽  
Author(s):  
Nace L. Golding ◽  
William L. Kath ◽  
Nelson Spruston
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Resting Potential ◽  
Model Parameters ◽  
Voltage Sensitivity ◽  
Whole Cell ◽  
Ca1 Pyramidal Neurons ◽  
Whole Cell Recordings

In hippocampal CA1 pyramidal neurons, action potentials are typically initiated in the axon and backpropagate into the dendrites, shaping the integration of synaptic activity and influencing the induction of synaptic plasticity. Despite previous reports describing action-potential propagation in the proximal apical dendrites, the extent to which action potentials invade the distal dendrites of CA1 pyramidal neurons remains controversial. Using paired somatic and dendritic whole cell recordings, we find that in the dendrites proximal to 280 μm from the soma, single backpropagating action potentials exhibit <50% attenuation from their amplitude in the soma. However, in dendritic recordings distal to 300 μm from the soma, action potentials in most cells backpropagated either strongly (26–42% attenuation; n = 9/20) or weakly (71–87% attenuation; n = 10/20) with only one cell exhibiting an intermediate value (45% attenuation). In experiments combining dual somatic and dendritic whole cell recordings with calcium imaging, the amount of calcium influx triggered by backpropagating action potentials was correlated with the extent of action-potential invasion of the distal dendrites. Quantitative morphometric analyses revealed that the dichotomy in action-potential backpropagation occurred in the presence of only subtle differences in either the diameter of the primary apical dendrite or branching pattern. In addition, action-potential backpropagation was not dependent on a number of electrophysiological parameters (input resistance, resting potential, voltage sensitivity of dendritic spike amplitude). There was, however, a striking correlation of the shape of the action potential at the soma with its amplitude in the dendrite; larger, faster-rising, and narrower somatic action potentials exhibited more attenuation in the distal dendrites (300–410 μm from the soma). Simple compartmental models of CA1 pyramidal neurons revealed that a dichotomy in action-potential backpropagation could be generated in response to subtle manipulations of the distribution of either sodium or potassium channels in the dendrites. Backpropagation efficacy could also be influenced by local alterations in dendritic side branches, but these effects were highly sensitive to model parameters. Based on these findings, we hypothesize that the observed dichotomy in dendritic action-potential amplitude is conferred primarily by differences in the distribution, density, or modulatory state of voltage-gated channels along the somatodendritic axis.

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.

scholarly journals Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

2020 ◽  
Vol 152 (5) ◽  
Author(s):  
Clara Inés McCarthy ◽  
Cambria Chou-Freed ◽  
Silvia Susana Rodríguez ◽  
Agustín Yaneff ◽  
Carlos Davio ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Intraperitoneal Administration ◽  
Brain Slices ◽  
Physiological Role ◽  
Receptor Type ◽  
Constitutive Activity ◽  
Medial Pfc

Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents’ sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons.

scholarly journals Developmental Regulation of Basket Interneuron Synapses and Behavior through NCAM in Mouse Prefrontal Cortex

2020 ◽  
Vol 30 (8) ◽  
pp. 4689-4707
Author(s):  
Chelsea S Sullivan ◽  
Vishwa Mohan ◽  
Paul B Manis ◽  
Sheryl S Moy ◽  
Young Truong ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
Developmental Regulation ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Electrophysiological Recording ◽  
Network Function ◽  
Growth Cone Collapse ◽  
Layer 2 ◽  
And Behavior

Abstract Parvalbumin (PV)-expressing basket interneurons in the prefrontal cortex (PFC) regulate pyramidal cell firing, synchrony, and network oscillations. Yet, it is unclear how their perisomatic inputs to pyramidal neurons are integrated into neural circuitry and adjusted postnatally. Neural cell adhesion molecule NCAM is expressed in a variety of cells in the PFC and cooperates with EphrinA/EphAs to regulate inhibitory synapse density. Here, analysis of a novel parvalbumin (PV)-Cre: NCAM F/F mouse mutant revealed that NCAM functions presynaptically in PV+ basket interneurons to regulate postnatal elimination of perisomatic synapses. Mutant mice exhibited an increased density of PV+ perisomatic puncta in PFC layer 2/3, while live imaging in mutant brain slices revealed fewer puncta that were dynamically eliminated. Furthermore, EphrinA5-induced growth cone collapse in PV+ interneurons in culture depended on NCAM expression. Electrophysiological recording from layer 2/3 pyramidal cells in mutant PFC slices showed a slower rise time of inhibitory synaptic currents. PV-Cre: NCAM F/F mice exhibited impairments in working memory and social behavior that may be impacted by altered PFC circuitry. These findings suggest that the density of perisomatic synapses of PV+ basket interneurons is regulated postnatally by NCAM, likely through EphrinA-dependent elimination, which is important for appropriate PFC network function and behavior.

Prolonged Synaptic Integration in Perirhinal Cortical Neurons

2000 ◽  
Vol 83 (6) ◽  
pp. 3294-3298 ◽  
Author(s):  
John M. Beggs ◽  
James R. Moyer ◽  
John P. McGann ◽  
Thomas H. Brown
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Perirhinal Cortex ◽  
Visually Guided ◽  
Time Intervals ◽  
Current Step ◽  
Long Time ◽  
Temporal Learning ◽  
Whole Cell Recordings

Layer II/III of rat perirhinal cortex (PR) contains numerous late-spiking (LS) pyramidal neurons. When injected with a depolarizing current step, these LS cells typically delay spiking for one or more seconds from the onset of the current step and then sustain firing for the duration of the step. This pattern of delayed and sustained firing suggested a specific computational role for LS cells in temporal learning. This hypothesis predicts and requires that some layer II/III neurons should also exhibit delayed and sustained spiking in response to a train of excitatory synaptic inputs. Here we tested this prediction using visually guided, whole cell recordings from rat PR brain slices. Most LS cells (19 of 26) exhibited delayed spiking to synaptic stimulation (>1 s latency from the train onset), and the majority of these cells (13 of 19) also showed sustained firing that persisted for the duration of the synaptic train (5–10 s duration). Delayed and sustained firing in response to long synaptic trains has not been previously reported in vertebrate neurons. The data are consistent with our model that a circuit containing late spiking neurons can be used for encoding long time intervals during associative learning.

scholarly journals The NMDA-to-AMPA Ratio at Synapses Onto Layer 2/3 Pyramidal Neurons Is Conserved Across Prefrontal and Visual Cortices

2003 ◽  
Vol 90 (2) ◽  
pp. 771-779 ◽  
Author(s):  
Chaelon I. O. Myme ◽  
Ken Sugino ◽  
Gina G. Turrigiano ◽  
Sacha B. Nelson
Keyword(s):  
Ampa Receptor ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Cell Voltage ◽  
Decay Kinetics ◽  
Excitatory Transmission ◽  
Layer 2 ◽  
Medial Pfc

To better understand regulation of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complements across the cortex, and to investigate NMDA receptor (NMDAR)-based models of persistent activity, we compared NMDA/AMPA ratios in prefrontal (PFC) and visual cortex (VC) in rat. Whole cell voltage-clamp responses were recorded in brain slices from layer 2/3 pyramidal cells of the medial PFC and VC of rats aged p16–p21. Mixed miniature excitatory postsynaptic currents (mEPSCs) having AMPA receptor (AMPAR)- and NMDAR-mediated components were isolated in nominally 0 Mg2+ ACSF. Averaged mEPSCs were well-fit by double exponentials. No significant differences in the NMDA/AMPA ratio (PFC: 27 ± 1%; VC: 28 ± 3%), peak mEPSC amplitude (PFC: 19.1 ± 1 pA; VC: 17.5 ± 0.7 pA), NMDAR decay kinetics (PFC: 69 ± 8 ms; VC: 67 ± 6 ms), or degree of correlation between NMDAR- and AMPAR-mediated mEPSC components were found between the areas (PFC: n = 27; VC: n = 28). Recordings from older rats (p26–29) also showed no differences. EPSCs were evoked extracellularly in 2 mM Mg2+ at depolarized potentials; although the average NMDA/AMPA ratio was larger than that observed for mEPSCs, the ratio was similar in the two regions. In nominally 0 Mg2+ and in the presence of CNQX, spontaneous activation of NMDAR increased recording noise and produced a small tonic depolarization which was similar in both areas. We conclude that this basic property of excitatory transmission is conserved across PFC and VC synapses and is therefore unlikely to contribute to differences in firing patterns observed in vivo in the two regions.

scholarly journals Functional CB1 Receptors Are Broadly Expressed in Neocortical GABAergic and Glutamatergic Neurons

2007 ◽  
Vol 97 (4) ◽  
pp. 2580-2589 ◽  
Author(s):  
Elisa L. Hill ◽  
Thierry Gallopin ◽  
Isabelle Férézou ◽  
Bruno Cauli ◽  
Jean Rossier ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Cannabinoid Receptor ◽  
Physiological Data ◽  
Glutamatergic Neurons ◽  
Neuronal Populations ◽  
Postsynaptic Currents ◽  
Neocortical Neurons ◽  
Neuronal Types ◽  
Cb1 Antagonist ◽  
Whole Cell Recordings

The cannabinoid receptor CB1 is found in abundance in brain neurons, whereas CB2 is essentially expressed outside the brain. In the neocortex, CB1 is observed predominantly on large cholecystokinin (CCK)-expressing interneurons. However, physiological evidence suggests that functional CB1 are present on other neocortical neuronal types. We investigated the expression of CB1 and CB2 in identified neurons of rat neocortical slices using single-cell RT-PCR. We found that 63% of somatostatin (SST)-expressing and 69% of vasoactive intestinal polypeptide (VIP)-expressing interneurons co-expressed CB1. As much as 49% of pyramidal neurons expressed CB1. In contrast, CB2 was observed in a small proportion of neocortical neurons. We performed whole cell recordings of pyramidal neurons to corroborate our molecular findings. Inhibitory postsynaptic currents (IPSCs) induced by a mixed muscarinic/nicotinic cholinergic agonist showed depolarization-induced suppression of inhibition and were decreased by the CB1 agonist WIN-55212-2 (WIN-2), suggesting that interneurons excited by cholinergic agonists (mainly SST and VIP neurons) possess CB1. IPSCs elicited by a nicotinic receptor agonist were also reduced in the presence of WIN-2, suggesting that neurons excited by nicotinic agonists (mainly VIP neurons) indeed possess CB1. WIN-2 largely decreased excitatory postsynaptic currents evoked by intracortical electrical stimulation, pointing at the presence of CB1 on glutamatergic pyramidal neurons. All WIN-2 effects were strongly reduced by the CB1 antagonist AM 251. We conclude that CB1 is expressed in various neocortical neuronal populations, including glutamatergic neurons. Our combined molecular and physiological data suggest that CB1 widely mediates endocannabinoid effects on glutamatergic and GABAergic transmission to modulate cortical networks.

Development of Intrinsic Properties and Excitability of Layer 2/3 Pyramidal Neurons During a Critical Period for Sensory Maps in Rat Barrel Cortex

2004 ◽  
Vol 92 (1) ◽  
pp. 144-156 ◽  
Author(s):  
Miguel Maravall ◽  
Edward A. Stern ◽  
Karel Svoboda
Keyword(s):  
Critical Period ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Pyramidal Cells ◽  
Membrane Properties ◽  
Sensory Maps ◽  
Layer 2 ◽  
Whole Cell Recordings ◽  
Passive Membrane Properties

The development of layer 2/3 sensory maps in rat barrel cortex (BC) is experience dependent with a critical period around postnatal days (PND) 10–14. The role of intrinsic response properties of neurons in this plasticity has not been investigated. Here we characterize the development of BC layer 2/3 intrinsic responses to identify possible sites of plasticity. Whole cell recordings were performed on pyramidal cells in acute BC slices from control and deprived rats, over ages spanning the critical period (PND 12, 14, and 17). Vibrissa trimming began at PND 9. Spiking behavior changed from phasic (more spike frequency adaptation) to regular (less adaptation) with age, such that the number of action potentials per stimulus increased. Changes in spiking properties were related to the strength of a slow Ca2+-dependent afterhyperpolarization. Maturation of the spiking properties of layer 2/3 pyramidal neurons coincided with the close of the critical period and was delayed by deprivation. Other measures of excitability, including I-f curves and passive membrane properties, were affected by development but unaffected by whisker deprivation.

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