Mechanisms of Dopamine Activation of Fast-Spiking Interneurons That Exert Inhibition in Rat Prefrontal Cortex

2002 ◽  
Vol 88 (6) ◽  
pp. 3150-3166 ◽  
Author(s):  
Natalia Gorelova ◽  
Jeremy K. Seamans ◽  
Charles R. Yang
Keyword(s):  
Prefrontal Cortex ◽  
Receptor Antagonist ◽  
Pyramidal Neurons ◽  
Sch 23390 ◽  
Membrane Depolarization ◽  
Inward Rectifier ◽  
Repetitive Firing ◽  
Gabaergic Interneurons ◽  
Fast Spiking

Prefrontal cortical dopamine (DA) modulates pyramidal cell excitability directly and indirectly by way of its actions on local circuit GABAergic interneurons. DA modulation of interneuronal functions is implicated in the computational properties of prefrontal networks during cognitive processes and in schizophrenia. Morphologically and electrophysiologically distinct classes of putative GABAergic interneurons are found in layers II-V of rat prefrontal cortex. Our whole cell patch-clamp study shows that DA induced a direct, TTX-insensitive, reversible membrane depolarization, and increased the excitability of fast-spiking (FS) interneurons. The DA-induced membrane depolarization was reduced significantly by D1/D5 receptor antagonist SCH 23390, but not by the D2 receptor antagonist (−)sulpiride, D4 receptor antagonists U101958 or L-745870, α1-adrenoreceptor antagonist prazosin, or serotoninergic receptor antagonist mianserin. The D1/5 agonists SKF81297 or dihydrexidine, but not D2 agonist quinpirole, also induced a prolonged membrane depolarization. Voltage-clamp analyses of the voltage-dependence of DA-sensitive currents, and the effects of changing [K+]O on reversal potentials of DA responses, revealed that DA suppressed a Cs+-sensitive inward rectifier K+ current and a resting leak K+ current. D1/D5, but not D2 agonists mimicked the suppressive effects of DA on the leak current, but the DA effects on the inward rectifier K+ current were not mimicked by either agonist. In a subgroup of FS interneurons, the slowly inactivating membrane outward rectification evoked by depolarizing voltage steps was also attenuated by DA. Collectively, these data showed that DA depolarizes FS interneurons by suppressing a voltage-independent ‘leak’ K+ current (via D1/D5 receptor mechanism) and an inwardly rectifying K+ current (via unknown DA mechanisms). Additional suppression of a slowly inactivating K+ current led to increase in repetitive firing in response to depolarizing inputs. This D1-induced increase in interneuron excitability enhances GABAergic transmission to PFC pyramidal neurons and could represent a mechanism via which DA suppresses persistent firing of pyramidal neurons in vivo.

scholarly journals Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

2020 ◽  
Author(s):  
Javier Zorrilla de San Martin ◽  
Cristina Donato ◽  
Jérémy Peixoto ◽  
Andrea Aguirre ◽  
Vikash Choudhary ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prefrontal Cortex ◽  
Cognitive Deficits ◽  
Pyramidal Neurons ◽  
Phase Locking ◽  
Network Activity ◽  
Inhibitory Circuits ◽  
Network Oscillations ◽  
Fast Spiking

AbstractDown syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

Dopamine Inhibition of Evoked IPSCs in Rat Prefrontal Cortex

2001 ◽  
Vol 86 (6) ◽  
pp. 2911-2918 ◽  
Author(s):  
Carlos Gonzalez-Islas ◽  
John J. Hablitz
Keyword(s):  
Prefrontal Cortex ◽  
Receptor Antagonist ◽  
Pyramidal Neurons ◽  
Sch 23390 ◽  
Experimental Studies ◽  
Pyramidal Cells ◽  
Cell Voltage ◽  
Cellular Level ◽  
Membrane Properties ◽  
Bath Application

Rat prefrontal cortex (PFC) receives substantial dopamine (DA) input. This DA innervation appears critical for modulation of PFC cognitive functions. Clinical and experimental studies have also implicated DA in the pathogenesis of a number of neurological and psychiatric disorders including epilepsy and schizophrenia. However, the actions of DA at the cellular level are incompletely understood. Both inhibitory interneurons and pyramidal cells are targets of DA and may express different DA receptor types. Our recent findings suggest that DA can directly excite cortical interneurons and increase the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). The present study was undertaken to determine the effect of specific DA receptor agonists on evoked (e) IPSCs. Visually identified pyramidal neurons were studied using whole cell voltage-clamp techniques. Bath application of DA 30 μM reduced IPSC amplitude to 80 ± 4% (mean ± SE) of control without any significant change in IPSC kinetics or passive membrane properties. The D1-like DA receptor agonist SKF 38393 reduced IPSC amplitude to 71.5 ± 8%, whereas the D2-like specific agonist quinpirole has no effect on amplitude (94.5 ± 5%). The D1-like receptor antagonist SCH 23390 prevented DA inhibition of IPSC amplitude (98.2 ± 4%), whereas IPSCs were still reduced in amplitude (79.7 ± 4%) by DA in the presence of the D2-like receptor antagonist sulpiride. DA increased significantly paired-pulse inhibition, whereas responses to puff applied GABA were unaffected. Addition of the PKA inhibitor H-8 blocked the effect of DA on IPSCs. These results suggest that DA can decrease IPSCs in layer II–III PFC neocortical pyramidal cells by activating presynaptic D1-like receptors.

scholarly journals Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Javier Zorrilla de San Martin ◽  
Cristina Donato ◽  
Jérémy Peixoto ◽  
Andrea Aguirre ◽  
Vikash Choudhary ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prefrontal Cortex ◽  
Cognitive Deficits ◽  
Pyramidal Neurons ◽  
Phase Locking ◽  
Network Activity ◽  
Inhibitory Circuits ◽  
Network Oscillations ◽  
Fast Spiking

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.

scholarly journals Amygdala inputs drive feedforward inhibition in the medial prefrontal cortex

2013 ◽  
Vol 110 (1) ◽  
pp. 221-229 ◽  
Author(s):  
Jonathan Dilgen ◽  
Hugo A. Tejeda ◽  
Patricio O'Donnell
Keyword(s):  
Prefrontal Cortex ◽  
Basolateral Amygdala ◽  
Pyramidal Neurons ◽  
Reversal Potential ◽  
Intracellular Recordings ◽  
Action Potential Firing ◽  
Gaba A ◽  
Potential Firing ◽  
Feedforward Inhibition

Although interactions between the amygdala and prefrontal cortex (PFC) are critical for emotional guidance of behavior, the manner in which amygdala affects PFC function is not clear. Whereas basolateral amygdala (BLA) output neurons exhibit many characteristics associated with excitatory neurotransmission, BLA stimulation typically inhibits PFC cell firing. This apparent discrepancy could be explained if local PFC inhibitory interneurons were activated by BLA inputs. Here, we used in vivo juxtacellular and intracellular recordings in anesthetized rats to investigate whether BLA inputs evoke feedforward inhibition in the PFC. Juxtacellular recordings revealed that BLA stimulation evoked action potentials in PFC interneurons and silenced most pyramidal neurons. Intracellular recordings from PFC pyramidal neurons showed depolarizing postsynaptic potentials, with multiple components evoked by BLA stimulation. These responses exhibited a relatively negative reversal potential (Erev), suggesting the contribution of a chloride component. Intracellular administration or pressure ejection of the GABA-A antagonist picrotoxin resulted in action-potential firing during the BLA-evoked response, which had a more depolarized Erev. These results suggest that BLA stimulation engages a powerful inhibitory mechanism within the PFC mediated by local circuit interneurons.

Modulation of voltage-dependent K+ currents (IK(V)) in retinal bipolar cells by ascorbate is mediated by dopamine D1 receptors

1999 ◽  
Vol 16 (5) ◽  
pp. 923-931 ◽  
Author(s):  
SHIH-FANG FAN ◽  
STEPHEN YAZULLA
Keyword(s):  
Receptor Antagonist ◽  
Glutamate Uptake ◽  
Sch 23390 ◽  
D2 Receptor ◽  
Bipolar Cells ◽  
D1 Receptors ◽  
Voltage Dependent ◽  
Average Latency

Ascorbic acid (AA), a neuromodulator in the vertebrate CNS, is released from glutamatergic neurons in exchange with glutamate uptake and, in turn, modulates the release of both glutamate and dopamine. We have reported that voltage-gated K+ currents (IK(V)) in ON-mixed rod/cone bipolar cells (Mb) were suppressed 60% by 100–200 μM AA when added to an ascorbate-free solution. However, as the in vivo [AA]o in retina is about 200 μM, we studied the effects of changes in [AA]o on IK(V) when [AA]o was varied around a baseline concentration of 200 μM. Whole-cell currents were recorded with patch-clamp methods from goldfish Mb cells in retinal slices, bathed in a solution containing 200 μM AA. We found that (1) IK(V) was enhanced (180 ± 36%, n = 9) by increases of [AA]o less than 40 μM with an average latency of 8 min. (2) However, IK(V) was suppressed without an appreciable latent period by two conditions: increases more than 40 μM [AA]o and decreases by any amount greater than 10 μM. (3) Effects of Δ[AA]o on IK(V) were blocked by a D1 dopamine receptor antagonist, SCH 23390, but not by a D2 receptor antagonist, spiperone. Increased concentrations of a D1 agonist (SKF 38390) and dopamine had similar concentration-dependent effects on IK(V) as did AA, even in the presence of 200 μM ascorbate. Ascorbate has complicated concentration-dependent effects on IK(V) of Mb cells in vitro that were mediated by D1 dopamine receptors, suggesting that dopamine and ascorbate may be involved reciprocally in modulating IK(V), with consequences on the transmission of rod signals to the inner retina.

scholarly journals Modulation of extracellular d-serine content by calcium permeable AMPA receptors in rat medial prefrontal cortex as revealed by in vivo microdialysis

2013 ◽  
Vol 16 (6) ◽  
pp. 1395-1406 ◽  
Author(s):  
Sayuri Ishiwata ◽  
Asami Umino ◽  
Masakazu Umino ◽  
Kazuko Yorita ◽  
Kiyoshi Fukui ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Receptor Antagonist ◽  
Medial Prefrontal Cortex ◽  
Glutamate Receptor ◽  
Ampa Receptor ◽  
In Vivo Microdialysis ◽  
Receptor Subtype ◽  
Fluorometric Detection ◽  
Brain Functions

Abstract In mammalian brains, d-serine has been shown to be required for the regulation of glutamate neurotransmission as an endogenous co-agonist for the N-methyl-d-aspartate type glutamate receptor that is essential for the expression of higher-order brain functions. The exact control mechanisms for the extracellular d-serine dynamics, however, await further elucidation. To obtain an insight into this issue, we have characterized the effects of agents acting at the α-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPA) type glutamate receptor on the extracellular d-serine contents in the medial prefrontal cortex of freely moving rats by an in vivo microdialysis technique in combination with high-performance liquid chromatography with fluorometric detection. In vivo experiments are needed in terms of a crucial role of d-serine in the neuron-glia communications despite the previous in vitro studies on AMPA receptor-d-serine interactions using the separated preparations of neurons or glial cells. Here, we show that the intra-cortical infusion of (S)-AMPA, an active enantiomer at the AMPA receptor, causes a significant and concentration-dependent reduction in the prefrontal extracellular contents of d-serine, which is reversed by an AMPA/kainate receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, and a calcium permeable AMPA receptor antagonist, 1-naphthyl acetyl spermine. The d-serine reducing effects of (S)-AMPA are augmented by co-infusion of cyclothiazide that prevents AMPA receptor desensitization. Our data support the view that a calcium permeable AMPA receptor subtype may exert a phasic inhibitory control on the extracellular d-serine release in the mammalian prefrontal cortex in vivo.

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