Dendritic release of glutamate suppresses synaptic inhibition of pyramidal neurons in rat neocortex

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

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Publisher Correction: Marked bias towards spontaneous synaptic inhibition distinguishes non-adapting from adapting layer 5 pyramidal neurons in the barrel cortex

Scientific Reports ◽

10.1038/s41598-017-18708-w ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Ion R. Popescu ◽

Kathy Q. Le ◽

Rocío Palenzuela ◽

Rebecca Voglewede ◽

Ricardo Mostany

Keyword(s):

Pyramidal Neurons ◽

Barrel Cortex ◽

Synaptic Inhibition

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Muscarinic Inhibition of Persistent Na+ Current in Rat Neocortical Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.1998.79.3.1579 ◽

1998 ◽

Vol 79 (3) ◽

pp. 1579-1582 ◽

Cited By ~ 45

Author(s):

Thomas Mittmann ◽

Christian Alzheimer

Keyword(s):

Pyramidal Neurons ◽

Pyramidal Cells ◽

Cholinergic Innervation ◽

Voltage Range ◽

Rat Neocortex ◽

The Rich ◽

Subthreshold Voltage ◽

Whole Cell Recordings ◽

Muscarinic Modulation ◽

Neocortical Pyramidal Neurons

Mittmann, Thomas and Christian Alzheimer. Muscarinic inhibition of persistent Na+ current in rat neocortical pyramidal neurons. J. Neurophysiol. 79: 1579–1582, 1998. Muscarinic modulation of persistent Na+ current ( I NaP) was studied using whole cell recordings from acutely isolated pyramidal cells of rat neocortex. After suppression of Ca2+ and K+ currents, I NaP was evoked by slow depolarizing voltage ramps or by long depolarizing voltage steps. The cholinergic agonist, carbachol, produced an atropine-sensitive decrease of I NaP at all potentials. When applied at a saturating concentration (20 μM), carbachol reduced peak I NaP by 38% on average. Carbachol did not alter the voltage dependence of I NaP activation nor did it interfere with the slow inactivation of I NaP. Our data indicate that I NaP can be targeted by the rich cholinergic innervation of the neocortex. Because I NaP is activated in the subthreshold voltage range, cholinergic inhibition of this current would be particularly suited to modulate the electrical behavior of neocortical pyramidal cells below and near firing threshold.

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Recruitment of GABAergic Inhibition and Synchronization of Inhibitory Interneurons in Rat Neocortex

Journal of Neurophysiology ◽

10.1152/jn.1997.77.6.3134 ◽

1997 ◽

Vol 77 (6) ◽

pp. 3134-3144 ◽

Cited By ~ 76

Author(s):

Larry S. Benardo

Keyword(s):

Large Amplitude ◽

Pyramidal Neurons ◽

Excitatory Amino Acid ◽

Lucifer Yellow ◽

Inhibitory Neurons ◽

Inhibitory Interneurons ◽

Gabaergic Inhibition ◽

Rat Neocortex ◽

Excitatory Gaba ◽

Spike Firing

Benardo, Larry S. Recruitment of GABAergic inhibition and synchronization of inhibitory interneurons in rat neocortex. J. Neurophysiol. 77: 3134–3144, 1997. Intracellular recordings were obtained from pyramidal and interneuronal cells in rat neocortical slices to examine the recruitment of GABAergic inhibition and inhibitory interneurons. In the presence of the convulsant agent4-aminopyridine (4-AP), after excitatory amino acid (EAA) ionotropic transmission was blocked, large-amplitude triphasic inhibitory postsynaptic potentials (IPSPs) occurred rhythmically (every 10–40 s) and synchronously in pyramidal neurons. After exposure to the γ-aminobutyric acid-A (GABAA) receptor antagonist picrotoxin, large-amplitude monophasic slow IPSPs persisted in these cells. In the presence of 4-AP and EAA blockers, interneurons showed periodic spike firing. Although some spikes rode on an underlying synaptic depolarization, much of the rhythmic firing consisted of spikes having highly variable amplitudes, arising abruptly from baseline, even during hyperpolarization. The spike firing and depolarizing synaptic potentials were completely suppressed by picrotoxin exposure, although monophasic slow IPSPs persisted in interneurons. This suggests that this subset of interneurons may participate in generating fast GABAA IPSPs, but not slow GABAB IPSPs. Cell morphology was confirmed by intracellular injection of neurobiotin or the fluorescent dye Lucifer yellow CH. Dye injection into interneurons often (>70%) resulted in the labeling of two to six cells (dye coupling). These findings suggest that GABAAergic neurons may be synchronized via recurrent collaterals through the depolarizing action of synaptically activatedGABAA receptors and a mechanism involving electrotonic coupling. Although inhibitory neurons mediating GABAB IPSPs may be entrained by the excitatory GABAA mechanism, they appear to be a separate subset of GABAergic neurons capable of functioning independently with autonomous pacing.

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Burst generating and regular spiking layer 5 pyramidal neurons of rat neocortex have different morphological features

The Journal of Comparative Neurology ◽

10.1002/cne.902960407 ◽

1990 ◽

Vol 296 (4) ◽

pp. 598-613 ◽

Cited By ~ 246

Author(s):

Yael Chagnac-Amitai ◽

Heiko J. Luhmann ◽

David A. Prince

Keyword(s):

Pyramidal Neurons ◽

Morphological Features ◽

Rat Neocortex

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GABAA Receptor α5 Subunits Contribute to GABAA,slow Synaptic Inhibition in Mouse Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.91203.2008 ◽

2009 ◽

Vol 101 (3) ◽

pp. 1179-1191 ◽

Cited By ~ 58

Author(s):

Ewa D. Zarnowska ◽

Ruth Keist ◽

Uwe Rudolph ◽

Robert A. Pearce

Keyword(s):

Cognitive Function ◽

Small Amplitude ◽

Drug Targets ◽

Pyramidal Neurons ◽

Aminobutyric Acid ◽

Synaptic Inhibition ◽

Wild Type ◽

Acid Type ◽

Mouse Hippocampus ◽

Potential Drug Targets

γ-Aminobutyric acid type A (GABAA) receptor α5 subunits, which are heavily expressed in the hippocampus, are potential drug targets for improving cognitive function. They are found at synaptic and extrasynaptic sites and have been shown to mediate tonic inhibition in pyramidal neurons. We tested the hypothesis that α5 subunits also contribute to synaptic inhibition by measuring the effect of diazepam (DZ) on spontaneous and stimulus-evoked inhibitory postsynaptic currents (IPSCs) in genetically modified mice carrying a point mutation in the α5 subunit (α5-H105R) that renders those receptors insensitive to benzodiazepines. In wild type mice, DZ (1 μM) increased the amplitude of spontaneous IPSCs (sIPSCs) and stimulus-evoked GABAA,slow IPSCs (eIPSCs) and prolonged the decay of GABAA,fast sIPSCs. In α5-mutant mice, DZ increased the amplitude of a small-amplitude subset of sIPSCs (<50 pA) and eIPSCs (<300 pA) GABAA,slow and prolonged the decay of GABAA,fast sIPSCs, but failed to increase the amplitude of larger sIPSCs and eIPSCs GABAA,slow. These results indicate that α5 subunits contribute to a large-amplitude subset of GABAA,slow synapses and implicate these synapses in modulation of cognitive function by drugs that target α5 subunits.

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