scholarly journals Effect of Nortriptyline on Spreading Depolarization

2020 ◽  
Vol 7 (3) ◽  
Author(s):  
Ebrahim Behzad ◽  
Mojdeh Ghabaee ◽  
Mohammad Reza Bigdeli ◽  
Farshid Noorbakhsh ◽  
Ali Gorji ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Neurological Diseases ◽  
Brain Slices ◽  
Lesion Size ◽  
Extracellular Potassium ◽  
Hippocampal Pyramidal Neurons ◽  
Electrophysiological Properties ◽  
Spreading Depolarization ◽  
Significant Difference ◽  
Molecular Aspects

Background: Spreading depolarization is associated with the extension of lesion size and complications in some important neurological diseases such as stroke, epilepsy, migraine, and traumatic brain injury. Objectives: This study aimed to reveal some molecular aspects of spreading depolarization and suggesting new therapeutic targets for its control by changing the function of different astrocytic and neuronal ion channels. Methods: The effects of nortriptyline on spreading depolarization in cortical and hippocampal tissues and on the electrophysiological properties of CA1 hippocampal pyramidal neurons were assessed by extra- and intracellular recording, following washing rat brain slices by the drug. Results: Nortriptyline made a significant increase in the amplitude of spreading depolarization in cortical and hippocampal tissues relative to control but did not change the duration significantly in each of the tissues. No significant difference was found in the effects of spreading depolarization on the electrophysiological properties of the CA1 pyramidal neurons between nortriptyline and control groups. Conclusions: The stimulating effect of nortriptyline on spreading depolarization is probably related to the augmentation of extracellular potassium collection in the cortex and hippocampus due to inhibition of astrocytic potassium scavenging function. This change can make more neurons prone to depolarization and increase the overall amplitude of spreading depolarization waves. Further studies should assess the effect of enhancing the clearance function of astrocyte-specific inwardly rectifying potassium channels, Kir4.1, or preventing other factors contributing to spreading depolarization on control of the process.

scholarly journals The antihelminthic moxidectin enhances tonic GABA currents in rodent hippocampal pyramidal neurons

2018 ◽  
Vol 119 (5) ◽  
pp. 1693-1698
Author(s):  
Jay Spampanato ◽  
Anne Gibson ◽  
F. Edward Dudek
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Gaba Receptors ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Companion Animals ◽  
Brain Slices ◽  
Dependent Manner ◽  
Hippocampal Pyramidal Neurons ◽  
Mammalian Central Nervous System

Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel “designer” ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors.NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.

scholarly journals Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca2+ dependence and differential modulation by norepinephrine

2015 ◽  
Vol 113 (7) ◽  
pp. 2014-2032 ◽  
Author(s):  
Dongxu Guan ◽  
William E. Armstrong ◽  
Robert C. Foehring
Keyword(s):  
Pyramidal Neurons ◽  
Fluorescent Protein ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Field Size ◽  
Repetitive Firing ◽  
Differential Modulation ◽  
Electrophysiological Properties ◽  
Laminar Distribution ◽  
Neocortical Pyramidal Neurons

We studied neocortical pyramidal neurons from two lines of bacterial artificial chromosome mice ( etv1 and glt; Gene Expression Nervous System Atlas: GENSAT project), each of which expresses enhanced green fluorescent protein (EGFP) in a different subpopulation of layer 5 pyramidal neurons. In barrel cortex, etv1 and glt pyramidal cells were previously reported to differ in terms of their laminar distribution, morphology, thalamic inputs, cellular targets, and receptive field size. In this study, we measured the laminar distribution of etv1 and glt cells. On average, glt cells were located more deeply; however, the distributions of etv1 and glt cells extensively overlap in layer 5. To test whether these two cell types differed in electrophysiological properties that influence firing behavior, we prepared acute brain slices from 2–4-wk-old mice, where EGFP-positive cells in somatosensory cortex were identified under epifluorescence and then studied using whole cell current- or voltage-clamp recordings. We studied the details of action potential parameters and repetitive firing, characterized by the larger slow afterhyperpolarizations (AHPs) in etv1 neurons and larger medium AHPs (mAHPS) in glt cells, and compared currents underlying the mAHP and slow AHP (sAHP) in etv1 and glt neurons. Etv1 cells exhibited lower d V/d t for spike polarization and repolarization and reduced direct current (DC) gain (lower f- I slope) for repetitive firing than glt cells. Most importantly, we found that 1) differences in the expression of Ca2+-dependent K+ conductances (small-conductance calcium-activated potassium channels and sAHP channels) determine major functional differences between etv1 and glt cells, and 2) there is differential modulation of etv1 and glt neurons by norepinephrine.

scholarly journals Intra-individual Physiomic Landscape of Pyramidal Neurons in the Human Neocortex

2021 ◽  
Author(s):  
Henrike Planert ◽  
Franz Xaver Mittermaier ◽  
Sabine Grosser ◽  
Pawel Fidzinski ◽  
Ulf Christoph Schneider ◽  
...  
Keyword(s):  
Pyramidal Neuron ◽  
Pyramidal Neurons ◽  
Phenotypic Variability ◽  
Temporal Cortex ◽  
Brain Slices ◽  
Individual Variability ◽  
Dimensional Parameter ◽  
Electrophysiological Properties ◽  
Synaptic Interactions ◽  
Organizational Principle

Computation within cortical microcircuits is determined by functional properties of the neurons and their synaptic interactions. While heterogeneity of inhibitory interneurons is well established, the anatomical, physiological, and molecular differentiation of excitatory pyramidal neurons is not fully resolved. To identify functional subtypes within the pyramidal neuron population, we focused on human layer 2-3 cortex which greatly expanded during evolution. We performed multi-neuron patch-clamp recordings in brain slices from the temporal cortex of 22 epilepsy patients. We characterized the electrophysiological properties of up to 80 pyramidal neurons per patient, enabling us to assess inter- and intra-individual functional variability. Hierarchical clustering of the high-dimensional parameter space yielded functionally distinct clusters of pyramidal neurons which were present across individuals. This may represent a generic organizational principle converging with previously described transcriptomic heterogeneity. We further observed substantial heterogeneity in physiological parameters with intra-individual variability being severalfold larger than inter-individual variability. The phenotypic variability within and across pyramidal neuron subtypes has important implications for the computational capacity of the cortical microcircuit. 

α5GABAA Receptors Regulate the Intrinsic Excitability of Mouse Hippocampal Pyramidal Neurons

2007 ◽  
Vol 98 (4) ◽  
pp. 2244-2254 ◽  
Author(s):  
Robert P. Bonin ◽  
Loren J. Martin ◽  
John F. MacDonald ◽  
Beverley A. Orser
Keyword(s):  
Action Potential ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Physiological Role ◽  
Network Activity ◽  
Equilibrium Potential ◽  
Resting Membrane Potential ◽  
Action Potential Firing ◽  
Membrane Hyperpolarization ◽  
Hippocampal Pyramidal Neurons

GABAA receptors generate both phasic and tonic forms of inhibition. In hippocampal pyramidal neurons, GABAA receptors that contain the α5 subunit generate a tonic inhibitory conductance. The physiological role of this tonic inhibition is uncertain, although α5GABAA receptors are known to influence hippocampal-dependent learning and memory processes. Here we provide evidence that α5GABAA receptors regulate the strength of the depolarizing stimulus that is required to generate an action potential in pyramidal neurons. Neurons from α5 knock-out (α5−/−) and wild-type (WT) mice were studied in brain slices and cell cultures using whole cell and perforated-patch-clamp techniques. Membrane resistance was 1.6-fold greater in α5−/− than in WT neurons, but the resting membrane potential and chloride equilibrium potential were similar. Membrane hyperpolarization evoked by an application of exogenous GABA was greater in WT neurons. Inhibiting the function of α5GABAA receptor with nonselective (picrotoxin) or α5 subunit-selective (L-655,708) compounds depolarized WT neurons by ∼3 mV, whereas no change was detected in α5−/− neurons. The depolarizing current required to generate an action potential was twofold greater in WT than in α5−/− neurons, whereas the slope of the input-output relationship for action potential firing was similar. We conclude that shunting inhibition mediated by α5GABAA receptors regulates the firing of action potentials and may synchronize network activity that underlies hippocampal-dependent behavior.

Alterations of the electrophysiological properties from cortical layer 5 pyramidal neurons in temporary rapamycin-treated rodent brain slices

2016 ◽  
Vol 612 ◽  
pp. 80-86 ◽  
Author(s):  
Keming Ren ◽  
Lijuan Chen ◽  
Guoxia Sheng ◽  
Jiangping Wang ◽  
Xiaoming Jin ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Brain Slices ◽  
Cortical Layer ◽  
Electrophysiological Properties ◽  
Rodent Brain

scholarly journals Development and validation of a potent and specific inhibitor for the CLC-2 chloride channel

2020 ◽  
Vol 117 (51) ◽  
pp. 32711-32721
Author(s):  
Anna K. Koster ◽  
Austin L. Reese ◽  
Yuri Kuryshev ◽  
Xianlan Wen ◽  
Keri A. McKiernan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Chloride Channel ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Specific Inhibitor ◽  
Kinetic Studies ◽  
Computational Docking ◽  
Hippocampal Pyramidal Neurons ◽  
The Central Nervous System

CLC-2 is a voltage-gated chloride channel that is widely expressed in mammalian tissues. In the central nervous system, CLC-2 appears in neurons and glia. Studies to define how this channel contributes to normal and pathophysiological function in the central nervous system raise questions that remain unresolved, in part due to the absence of precise pharmacological tools for modulating CLC-2 activity. Herein, we describe the development and optimization of AK-42, a specific small-molecule inhibitor of CLC-2 with nanomolar potency (IC50= 17 ± 1 nM). AK-42 displays unprecedented selectivity (>1,000-fold) over CLC-1, the closest CLC-2 homolog, and exhibits no off-target engagement against a panel of 61 common channels, receptors, and transporters expressed in brain tissue. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. In electrophysiological recordings of mouse CA1 hippocampal pyramidal neurons, AK-42 acutely and reversibly inhibits CLC-2 currents; no effect on current is observed on brain slices taken from CLC-2 knockout mice. These results establish AK-42 as a powerful tool for investigating CLC-2 neurophysiology.

scholarly journals Optogenetic Activation of Astrocytes—Effects on Neuronal Network Function

2021 ◽  
Vol 22 (17) ◽  
pp. 9613
Author(s):  
Evgenii Gerasimov ◽  
Alexander Erofeev ◽  
Anastasia Borodinova ◽  
Anastasia Bolshakova ◽  
Pavel Balaban ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Continuous Light ◽  
Hippocampal Pyramidal Neurons ◽  
Network Function ◽  
Stimulation Mode ◽  
Hippocampal Astrocytes

Optogenetics approach is used widely in neurobiology as it allows control of cellular activity with high spatial and temporal resolution. In most studies, optogenetics is used to control neuronal activity. In the present study optogenetics was used to stimulate astrocytes with the aim to modulate neuronal activity. To achieve this goal, light stimulation was applied to astrocytes expressing a version of ChR2 (ionotropic opsin) or Opto-α1AR (metabotropic opsin). Optimal optogenetic stimulation parameters were determined using patch-clamp recordings of hippocampal pyramidal neurons’ spontaneous activity in brain slices as a readout. It was determined that the greatest increase in the number of spontaneous synaptic currents was observed when astrocytes expressing ChR2(H134R) were activated by 5 s of continuous light. For the astrocytes expressing Opto-α1AR, the greatest response was observed in the pulse stimulation mode (T = 1 s, t = 100 ms). It was also observed that activation of the astrocytic Opto-a1AR but not ChR2 results in an increase of the fEPSP slope in hippocampal neurons. Based on these results, we concluded that Opto-a1AR expressed in hippocampal astrocytes provides an opportunity to modulate the long-term synaptic plasticity optogenetically, and may potentially be used to normalize the synaptic transmission and plasticity defects in a variety of neuropathological conditions, including models of Alzheimer’s disease and other neurodegenerative disorders.

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