Acute Clozapine Suppresses Synchronized Pyramidal Synaptic Network Activity by Increasing Inhibition in the Ferret Prefrontal Cortex

2007 ◽  
Vol 97 (2) ◽  
pp. 1196-1208 ◽  
Author(s):  
Wen-Jun Gao
Keyword(s):  
Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Suppressive Effect ◽  
Network Activity ◽  
Cortical Circuitry ◽  
Prefrontal Cortical ◽  
Recurrent Excitation ◽  
Whole Cell Recordings

Recent studies have indicated that impaired neural circuitry in the prefrontal cortex is a prominent feature of the neuropathology of schizophrenia. Clozapine is one of the most effective antipsychotic drugs used for this debilitating disease. Despite its effectiveness, the mechanism by which clozapine acts on prefrontal cortical circuitry remains poorly understood. In this study, in vitro multiple whole cell recordings were performed in slices of the ferret prefrontal cortex. Clozapine, which effectively inhibited the spontaneous synchronized network activities in the prefrontal neurons, achieved the suppressive effect by decreasing the recurrent excitation among pyramidal neurons and by enhancing the inhibitory inputs onto pyramidal cells through a likely network mechanism. Indeed, under the condition of disinhibition, the depressing effects were reversed and clozapine enhanced the recurrent excitation. These results suggest that the therapeutic actions of clozapine in alleviating the positive symptoms of schizophrenia are achieved, at least partially, through the readjustment of synaptic balance between the excitation and inhibition in the prefrontal cortical circuitry.

scholarly journals Dopamine Increases Excitability of Pyramidal Neurons in Primate Prefrontal Cortex

2000 ◽  
Vol 84 (6) ◽  
pp. 2799-2809 ◽  
Author(s):  
Darrell A. Henze ◽  
Guillermo R. González-Burgos ◽  
Nathaniel N. Urban ◽  
David A. Lewis ◽  
German Barrionuevo
Keyword(s):  
Prefrontal Cortex ◽  
Action Potential ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Initiation Site ◽  
D1 Receptor ◽  
Resting Membrane Potential ◽  
Cellular Mechanisms

Dopaminergic modulation of neuronal networks in the dorsolateral prefrontal cortex (PFC) is believed to play an important role in information processing during working memory tasks in both humans and nonhuman primates. To understand the basic cellular mechanisms that underlie these actions of dopamine (DA), we have investigated the influence of DA on the cellular properties of layer 3 pyramidal cells in area 46 of the macaque monkey PFC. Intracellular voltage recordings were obtained with sharp and whole cell patch-clamp electrodes in a PFC brain-slice preparation. All of the recorded neurons in layer 3 ( n = 86) exhibited regular spiking firing properties consistent with those of pyramidal neurons. We found that DA had no significant effects on resting membrane potential or input resistance of these cells. However DA, at concentrations as low as 0.5 μM, increased the excitability of PFC cells in response to depolarizing current steps injected at the soma. Enhanced excitability was associated with a hyperpolarizing shift in action potential threshold and a decreased first interspike interval. These effects required activation of D1-like but not D2-like receptors since they were inhibited by the D1 receptor antagonist SCH23390 (3 μM) but not significantly altered by the D2 antagonist sulpiride (2.5 μM). These results show, for the first time, that DA modulates the activity of layer 3 pyramidal neurons in area 46 of monkey dorsolateral PFC in vitro. Furthermore the results suggest that, by means of these effects alone, DA modulation would generally enhance the response of PFC pyramidal neurons to excitatory currents that reach the action potential initiation site.

scholarly journals Diversity amongst human cortical pyramidal neurons revealed via their sag currents and frequency preferences

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Homeira Moradi Chameh ◽  
Scott Rich ◽  
Lihua Wang ◽  
Fu-Der Chen ◽  
Liang Zhang ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Theta Oscillations ◽  
Cortical Layers ◽  
Electrophysiological Properties ◽  
Theta Frequency ◽  
Subthreshold Resonance ◽  
Cortical Pyramidal Neurons ◽  
Whole Cell Recordings

AbstractIn the human neocortex coherent interlaminar theta oscillations are driven by deep cortical layers, suggesting neurons in these layers exhibit distinct electrophysiological properties. To characterize this potential distinctiveness, we use in vitro whole-cell recordings from cortical layers 2 and 3 (L2&3), layer 3c (L3c) and layer 5 (L5) of the human cortex. Across all layers we observe notable heterogeneity, indicating human cortical pyramidal neurons are an electrophysiologically diverse population. L5 pyramidal cells are the most excitable of these neurons and exhibit the most prominent sag current (abolished by blockade of the hyperpolarization activated cation current, Ih). While subthreshold resonance is more common in L3c and L5, we rarely observe this resonance at frequencies greater than 2 Hz. However, the frequency dependent gain of L5 neurons reveals they are most adept at tracking both delta and theta frequency inputs, a unique feature that may indirectly be important for the generation of cortical theta oscillations.

scholarly journals Synaptic GABAA Activation Inhibits AMPA-Kainate Receptor–Mediated Bursting in the Newborn (P0–P2) Rat Hippocampus

2000 ◽  
Vol 83 (1) ◽  
pp. 359-366 ◽  
Author(s):  
Karri Lamsa ◽  
J. Matias Palva ◽  
Eva Ruusuvuori ◽  
Kai Kaila ◽  
Tomi Taira
Keyword(s):  
Pyramidal Neurons ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Neuronal Population ◽  
Excitatory Input ◽  
Calcium Oscillations ◽  
Rat Hippocampus ◽  
Network Activity ◽  
Ca1 Pyramidal Cells

The mechanisms of synaptic transmission in the rat hippocampus at birth are assumed to be fundamentally different from those found in the adult. It has been reported that in the CA3-CA1 pyramidal cells a conversion of “silent” glutamatergic synapses to conductive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) synapses starts gradually after P2. Further, GABA via its depolarizing action seems to give rise to grossly synchronous yet slow calcium oscillations. Therefore, GABA is generally thought to have a purely excitatory rather than an inhibitory role during the first postnatal week. In the present study field potential recordings and gramicidin perforated and whole cell clamp techniques as well as K+-selective microelectrodes were used to examine the relative contributions of AMPA and GABAA receptors to network activity of CA3-CA1 pyramidal cells in the newborn rat hippocampus. As early as postnatal day( P 0–P2), highly coherent spontaneous firing of CA3 pyramidal cells was seen in vitro. Negative-going extracellular spikes confined to periodic bursts (interval 16 ± 3 s) consisting of 2.9 ± 0.1 spikes were observed in stratum pyramidale. The spikes were accompanied by AMPA-R–mediated postsynaptic currents (PSCs) in simultaneously recorded pyramidal neurons (7.6 ± 3.0 unitary currents per burst). In CA1 pyramidal cells synchronous discharging of CA3 circuitry produced a barrage of AMPA currents at >20 Hz frequencies, thus demonstrating a transfer of the fast CA3 network activity to CA1 area. Despite its depolarizing action, GABAA-R–mediated transmission appeared to exert inhibition in the CA3 pyramidal cell population. The GABAA-R antagonist bicuculline hypersynchronized the output of glutamatergic CA3 circuitry and increased the network-driven excitatory input to the pyramidal neurons, whereas the GABAA-R agonist muscimol (100 nM) did the opposite. However, the occurrence of unitary GABAA-R currents was increased after muscimol application from 0.66 ± 0.16 s−1 to 1.43 ± 0.29 s−1. It was concluded that AMPA synapses are critical in the generation of spontaneous high-frequency bursts in CA3 as well as in CA3-CA1 transmission as early as P0–P2 in rat hippocampus. Concurrently, although GABAA-R–mediated depolarization may excite hippocampal interneurons, in CA3 pyramidal neurons it can restrain excitatory inputs and limit the size of the activated neuronal population.

Dopamine Increases the Gain of the Input-Output Response of Rat Prefrontal Pyramidal Neurons

2008 ◽  
Vol 99 (6) ◽  
pp. 2985-2997 ◽  
Author(s):  
Kay Thurley ◽  
Walter Senn ◽  
Hans-Rudolf Lüscher
Keyword(s):  
Working Memory ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
D1 Receptors ◽  
Input Output ◽  
Prefrontal Cortical ◽  
Noisy Input ◽  
Relationship Of

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

Effect of Common Anesthetics on Dendritic Properties in Layer 5 Neocortical Pyramidal Neurons

2008 ◽  
Vol 99 (3) ◽  
pp. 1394-1407 ◽  
Author(s):  
Sarah Potez ◽  
Matthew E. Larkum
Keyword(s):  
High Frequency ◽  
Pyramidal Neurons ◽  
Animal Experiments ◽  
Apical Dendrite ◽  
Network Activity ◽  
Calcium Spikes ◽  
Firing Properties ◽  
The Impact

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.

Differential Impact of Miniature Synaptic Potentials on the Soma and Dendrites of Pyramidal Neurons In Vivo

1997 ◽  
Vol 78 (3) ◽  
pp. 1735-1739 ◽  
Author(s):  
Denis Paré ◽  
Elen Lebel ◽  
Eric J. Lang
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Differential Impact ◽  
Synaptic Potentials ◽  
Ampa Antagonists ◽  
Intact Brain ◽  
The Impact

Paré, Denis, Elen LeBel, and Eric J. Lang. Differential impact of miniature synaptic potentials on the somata and dendrites of pyramidal neurons in vivo. J. Neurophysiol. 78: 1735–1739, 1997. We studied the impact of transmitter release resistant to tetrodotoxin (TTX) in morphologically identified neocortical pyramidal neurons recorded intracellularly in barbiturate-anesthetized cats. It was observed that TTX-resistant release occurs in pyramidal neurons in vivo and at much higher frequencies than was previously reported in vitro. Further, in agreement with previous findings indicating that GABAergic and glutamatergic synapses are differentially distributed in the somata and dendrites of pyramidal cells, we found that most miniature synaptic potentials were sensitive to γ-aminobutyric acid-A (GABAA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists in presumed somatic and dendritic impalements, respectively. Pharmacological blockage of spontaneous synaptic events produced large increases in input resistance that were more important in dendritic (≈50%) than somatic (≈10%) impalements. These findings imply that in the intact brain, pyramidal neurons are submitted to an intense spike-independent synaptic bombardment that decreases the space constant of the cells. These results should be taken into account when extrapolating in vitro findings to intact brains.

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.

scholarly journals Self-tuning of inhibition by endocannabinoids shapes spike-time precision in CA1 pyramidal neurons

2013 ◽  
Vol 110 (8) ◽  
pp. 1930-1944 ◽  
Author(s):  
Franck Dubruc ◽  
David Dupret ◽  
Olivier Caillard
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Memory Formation ◽  
Spike Timing ◽  
Excitatory Postsynaptic Potential ◽  
Spike Time ◽  
Transient Improvement ◽  
Self Tuning ◽  
Feedforward Inhibition

In the hippocampus, activity-dependent changes of synaptic transmission and spike-timing coordination are thought to mediate information processing for the purpose of memory formation. Here, we investigated the self-tuning of intrinsic excitability and spiking reliability by CA1 hippocampal pyramidal cells via changes of their GABAergic inhibitory inputs and endocannabinoid (eCB) signaling. Firing patterns of CA1 place cells, when replayed in vitro, induced an eCB-dependent transient reduction of spontaneous GABAergic activity, sharing the main features of depolarization-induced suppression of inhibition (DSI), and conditioned a transient improvement of spike-time precision during consecutive burst discharges. When evaluating the consequences of DSI on excitatory postsynaptic potential (EPSP)-spike coupling, we found that transient reductions of uncorrelated (spontaneous) or correlated (feedforward) inhibition improved EPSP-spike coupling probability. The relationship between EPSP-spike-timing reliability and inhibition was, however, more complex: transient reduction of correlated (feedforward) inhibition disrupted or improved spike-timing reliability according to the initial spike-coupling probability. Thus eCB-mediated tuning of pyramidal cell spike-time precision is governed not only by the initial level of global inhibition, but also by the ratio between spontaneous and feedforward GABAergic activities. These results reveal that eCB-mediated self-tuning of spike timing by the discharge of pyramidal cells can constitute an important contribution to place-cell assemblies and memory formation in the hippocampus.

Spike Timing of Lacunosom-Moleculare Targeting Interneurons and CA3 Pyramidal Cells During High-Frequency Network Oscillations In Vitro

2007 ◽  
Vol 98 (1) ◽  
pp. 96-104 ◽  
Author(s):  
Jay Spampanato ◽  
Istvan Mody
Keyword(s):  
High Frequency ◽  
Epileptiform Activity ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Gamma Oscillations ◽  
Spike Timing ◽  
Network Activity ◽  
Network Oscillations ◽  
Ca3 Pyramidal Cells

Network activity in the 200- to 600-Hz range termed high-frequency oscillations (HFOs) has been detected in epileptic tissue from both humans and rodents and may underlie the mechanism of epileptogenesis in experimental rodent models. Slower network oscillations including theta and gamma oscillations as well as ripples are generated by the complex spike timing and interactions between interneurons and pyramidal cells of the hippocampus. We determined the activity of CA3 pyramidal cells, stratum oriens lacunosum-moleculare (O-LM) and s. radiatum lacunosum-moleculare (R-LM) interneurons during HFO in the in vitro low-Mg2+ model of epileptiform activity in GIN mice. In these animals, interneurons can be identified prior to cell-attached recordings by the expression of green-fluorescent protein (GFP). Simultaneous local field potential recordings from s. pyramidale and on-cell recordings of individual interneurons and principal cells revealed three primary firing behaviors of the active cells: 36% of O-LM interneurons and 60% of pyramidal cells fired action potentials at high frequencies during the HFO. R-LM interneurons were biphasic in that they fired at high frequency at the beginning of the HFO but stopped firing before its end. When considering only the highest frequency component of the oscillations most pyramidal cells fired on the rising phase of the oscillation. These data provide evidence for functional distinction during HFOs within otherwise homogeneous groups of O-LM interneurons and pyramidal cells.

scholarly journals Dopaminergic Modulation of Local Network Activity in Rat Prefrontal Cortex

2007 ◽  
Vol 97 (6) ◽  
pp. 4120-4128 ◽  
Author(s):  
Susanta Bandyopadhyay ◽  
John J. Hablitz
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Transmission ◽  
Receptor Agonist ◽  
Neuronal Networks ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Lateral Spread ◽  
Local Network ◽  
Evoked Activity

Dopamine modulates prefrontal cortex excitability in complex ways. Dopamine's net effect on local neuronal networks is therefore difficult to predict based on studies on pharmacologically isolated excitatory or inhibitory connections. In the present work, we have studied the effects of dopamine on evoked activity in acute rat brain slices when both excitation and inhibition are intact. Whole cell recordings from layer II/III pyramidal cells under conditions of normal synaptic transmission showed that bath-applied dopamine (30 μM) increased the outward inhibitory component of composite postsynaptic currents, whereas inward excitatory currents were not significantly affected. Optical imaging with the voltage-sensitive dye N-(3-(triethylammonium)propyl)-4-(4-(p-diethylaminophenyl)buta-dienyl)pyridinium dibromide revealed that bath application of dopamine significantly decreased the amplitude, duration, and lateral spread of activity in local cortical networks. This effect of dopamine was observed both with single and train (5 at 20 Hz) stimuli. The effect was mimicked by the D1-like receptor agonist R(+)-6-chloro-7,8-dihydroxy-1-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1 μM) and was blocked by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (10 μM), a selective antagonist for D1-like receptors. The D2-like receptor agonist quinpirole (10 μM) had no significant effect on evoked dye signals. Our results suggest that dopamine's effect on inhibition dominates over that on excitation under conditions of normal synaptic transmission. Such neuromodulation by dopamine may be important for maintenance of stability in local neuronal networks in the prefrontal cortex.

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