Metabolic Challenge to Glia Activates an Adenosine-Mediated Safety Mechanism that Promotes Neuronal Survival by Delaying the Onset of Spreading Depression Waves

In a model of glial-specific chemical anoxia, we have examined how astrocytes influence both synaptic transmission and the viability of hippocampal pyramidal neurons. This relationship was assessed using electrophysiological, pharmacological, and biochemical techniques in rat slices and cell cultures, and oxidative metabolism was selectively impaired in glial cells by exposure to the mitochondrial gliotoxin, fluoroacetate. We found that synaptic transmission was blocked shortly after inducing glial metabolic stress and peri-infarct-like spreading depression (SD) waves developed within 1 to 2 h of treatment. Neuronal electrogenesis was not affected until SD waves developed, thereafter decaying irreversibly. The blockage of synaptic transmission was totally reversed by A1 adenosine receptor antagonists, unlike the development of SD waves, which appeared earlier under these conditions. Such blockage led to a marked reduction in the electrical viability of pyramidal neurons 1 h after gliotoxin treatment. Cell culture experiments confirmed that astrocytes indeed release adenosine. We interpret this early glial response as a novel safety mechanism that allocates metabolic resources to vital processes when the glia itself sense an energy shortage, thereby delaying or preventing entry into massive lethal ischemic-like depolarization. The implication of these results on the functional recovery of the penumbra regions after ischemic insults is discussed.

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Two Mechanisms That Raise Free Intracellular Calcium in Rat Hippocampal Neurons During Hypoosmotic and Low NaCl Treatment

Journal of Neurophysiology ◽

10.1152/jn.2000.83.1.81 ◽

2000 ◽

Vol 83 (1) ◽

pp. 81-89 ◽

Cited By ~ 18

Author(s):

Aren J. Borgdorff ◽

George G. Somjen ◽

Wytse J. Wadman

Keyword(s):

Synaptic Transmission ◽

Intracellular Calcium ◽

Hippocampal Neurons ◽

Pyramidal Neurons ◽

Hippocampal Slices ◽

Cell Swelling ◽

Tissue Slices ◽

Extracellular Medium ◽

Calcium Activity ◽

Hippocampal Pyramidal Neurons

Previous studies have shown that exposing hippocampal slices to low osmolarity (πo) or to low extracellular NaCl concentration ([NaCl]o) enhances synaptic transmission and also causes interstitial calcium ([Ca2+]o) to decrease. Reduction of [Ca2+]o suggests cellular uptake and could explain the potentiation of synaptic transmission. We measured intracellular calcium activity ([Ca2+]i) using fluorescent indicator dyes. In CA1 hippocampal pyramidal neurons in tissue slices, lowering πo by ∼70 mOsm caused “resting” [Ca2+]i as well as synaptically or directly stimulated transient increases of calcium activity (Δ[Ca2+]i) to transiently decrease and then to increase. In dissociated cells, lowering πo by ∼70 mOsm caused [Ca2+]i to almost double on average from 83 to 155 nM. The increase of [Ca2+]i was not significantly correlated with hypotonic cell swelling. Isoosmotic (mannitol- or sucrose-substituted) lowering of [NaCl]o, which did not cause cell swelling, also raised [Ca2+]i. Substituting NaCl with choline-Cl or Na-methyl-sulfate did not affect [Ca2+]i. In neurons bathed in calcium-free medium, lowering πo caused a milder increase of [Ca2+]i, which was correlated with cell swelling, but in the absence of external Ca2+, isotonic lowering of [NaCl]o triggered only a brief, transient response. We conclude that decrease of extracellular ionic strength (i.e., in both low πo and low [NaCl]o) causes a net influx of Ca2+ from the extracellular medium whereas cell swelling, or the increase in membrane tension, is a signal for the release of Ca2+ from intracellular stores.

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Heptanol But Not Fluoroacetate Prevents the Propagation of Spreading Depression in Rat Hippocampal Slices

Journal of Neurophysiology ◽

10.1152/jn.1997.77.1.9 ◽

1997 ◽

Vol 77 (1) ◽

pp. 9-16 ◽

Cited By ~ 54

Author(s):

Carlota Largo ◽

Geoffrey C. Tombaugh ◽

Peter G. Aitken ◽

Oscar Herreras ◽

George G. Somjen

Keyword(s):

Synaptic Transmission ◽

Gap Junctions ◽

Spreading Depression ◽

Pyramidal Neurons ◽

Hippocampal Slices ◽

Lipid Phase ◽

Tissue Slices ◽

Population Spikes ◽

Afferent Volleys ◽

Stimulation Of

Largo, Carlota, Geoffrey C. Tombaugh, Peter G. Aitken, Oscar Herreras, and George G. Somjen. Heptanol but not fluoroacetate prevents the propagation of spreading depression in rat hippocampal slices. J. Neurophysiol. 77: 9–16, 1997. We investigated whether heptanol and other long-chain alcohols that are known to block gap junctions interfere with the generation or the propagation of spreading depression (SD). Waves of SD were triggered by micro-injection of concentrated KCl solution in stratum (s.) radiatum of CA1 of rat hippocampal tissue slices. DC-coupled recordings of extracellular potential ( V o) were made at the injection and at a second site ∼1 mm distant in st. radiatum and sometimes also in st. pyramidale. Extracellular excitatory postsynaptic potentials (fEPSPs) were evoked by stimulation of the Schaffer collateral bundle; in some experiments, antidromic population spikes were evoked by stimulation of the alveus. Bath application of 3 mM heptanol or 5 mM hexanol completely and reversibly prevented the propagation of the SD-related potential shift (Δ V o) without abolishing the Δ V o at the injection site. Octanol (1 mM) had a similar but less reliably reversible effect. fEPSPs were depressed by ∼30% by heptanol and octanol, 65% by hexanol. Antidromic population spikes were depressed by 30%. In isolated, patch-clamped CA1 pyramidal neurons, heptanol partially and reversibly depressed voltage-dependent Na currents possibly explaining the slight depression of antidromic spikes and, by acting on presynaptic action potentials, also the depression of fEPSPs. Fluoroacetate (FAc), a putative selective blocker of glial metabolism, first induced multiple spike firing in response to single afferent volleys and then severely suppressed synaptic transmission (confirming earlier reports) without depressing the antidromic population spike. FAc did not inhibit SD propagation. The effect of alkyl alcohols is compatible with the idea that the opening of normally closed neuronal gap junctions is required for SD propagation. Alternative possible explanations include interference with the lipid phase of neuron membranes. The absence of SD inhibition by FAc confirms that synaptic transmission is not necessary for the propagation of SD, and it suggests that normally functioning glial cells are not essential for SD generation or propagation.

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NMDA receptor activation enhances inhibitory synaptic transmission in hippocampal pyramidal neurons

Neuroscience Research ◽

10.1016/j.neures.2009.09.263 ◽

2009 ◽

Vol 65 ◽

pp. S74

Author(s):

Jiugang Xue ◽

Sai-Kit Alex Law ◽

Shiro Konishi

Keyword(s):

Nmda Receptor ◽

Synaptic Transmission ◽

Pyramidal Neurons ◽

Receptor Activation ◽

Hippocampal Pyramidal Neurons ◽

Inhibitory Synaptic Transmission ◽

Nmda Receptor Activation

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Anti-Müllerian Hormone Regulation of Synaptic Transmission in the Hippocampus Requires MAPK Signaling and Kv4.2 Potassium Channel Activity

Frontiers in Neuroscience ◽

10.3389/fnins.2021.772251 ◽

2021 ◽

Vol 15 ◽

Author(s):

Kang Wang ◽

Fuhua Xu ◽

James Maylie ◽

Jing Xu

Keyword(s):

Synaptic Transmission ◽

P38 Mapk ◽

Pyramidal Neurons ◽

Hippocampal Slices ◽

Mapk Signaling ◽

Dependent Manner ◽

Hormone Regulation ◽

Paracrine Factor ◽

Specific Expression ◽

Hippocampal Pyramidal Neurons

Anti-Müllerian hormone (AMH) is a paracrine factor generated peripherally by the gonads to regulate gonadal function in adult mammals. We recently reported that AMH and AMH-specific receptor Anti-Müllerian hormone receptor 2 (AMHR2) are expressed in the hippocampus, and exogenous AMH protein rapidly increased synaptic transmission and long-term synaptic plasticity at the CA3-CA1 synapses. Here we examined the cell-specific expression of AMHR2 and the cellular mechanism of rapid boosting effect of AMH on synaptic transmission in mouse hippocampus. Immunofluorescence staining showed that AMHR2 was specifically expressed in the soma and dendrites of hippocampal pyramidal neurons, but not glial cells. Electrophysiological recordings on acute hippocampal slices showed that AMH did not affect AMPAR-mediated or N-Methyl-D-aspartic acid receptor (NMDAR)-mediated excitatory postsynaptic currents at the CA3-CA1 synapses. The small-conductance Ca2+-activated K+ channel (SK2) and A-type K+ channel (Kv4.2) contribute to shaping excitatory postsynaptic potentials (EPSPs) at the CA3-CA1 synapses. Bath application of apamin to block SK2 did not alter AMH effect on increasing EPSPs, whereas blocking Kv4.2 channel with 4-aminopyridine, or chelating internal Ca2+ with BAPTA occluded the action of AMH on boosting EPSPs. Kv4.2 activity is regulated by p38 mitogen-activated kinase (MAPK). Blocking p38 MAPK with SB203580 occluded the effect of AMH on increasing EPSPs. These results show that Kv4.2 channel contributes to the rapid action of AMH on boosting synaptic transmission in a Ca2+- and p38 MAPK-dependent manner. Our findings provide functional evidence that AMH enhances synaptic transmission through Kv4.2 channel in the hippocampus, suggesting a possible role of Kv4.2 channel in AMH-regulated neuronal process underlying learning and memory.

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Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Brain Sciences ◽

10.3390/brainsci10100706 ◽

2020 ◽

Vol 10 (10) ◽

pp. 706

Author(s):

Wen-Bing Chen ◽

Jiang Chen ◽

Zi-Yang Liu ◽

Bin Luo ◽

Tian Zhou ◽

...

Keyword(s):

Synaptic Transmission ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Glutamate Release ◽

Hippocampal Slices ◽

Hippocampal Pyramidal Neurons ◽

Beneficial Effects ◽

Ca1 Pyramidal Neurons ◽

Postsynaptic Currents ◽

Hippocampal Ca1

Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

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