NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

2001 ◽  
Vol 280 (6) ◽  
pp. R1815-R1822 ◽  
Author(s):  
Javier E. Stern ◽  
Mike Ludwig
Keyword(s):  
Neuronal Excitability ◽  
Cell Types ◽  
Synaptic Activity ◽  
No Donor ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Neuronal Types ◽  
Vasopressin Neurons

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

Nitric Oxide Modulation of Supraoptic Oxytocin and Vasopressin Neurons Involves Potentiation of Gabaergic Synaptic Inputs.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 700-700
Author(s):  
Javier E Stern ◽  
Mike Ludwig
Keyword(s):  
Nitric Oxide ◽  
Synaptic Activity ◽  
Cellular Mechanisms ◽  
Synaptic Currents ◽  
No Donor ◽  
Salt Loading ◽  
Inhibitory Feedback ◽  
Vasopressin Neurons

P41 There is growing evidence that nitric oxide (NO) in the central nervous system functions as a local neuromodulator in water balance and osmotic regulation. However, the precise mechanisms by which these actions are mediated are still poorly understood. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in the supraoptic (SON) and paraventricular (PVN) nuclei. nNOS expression is up-regulated in conditions known to stimulate oxytocin (OT) and vasopressin (VP) hormone release, such as salt loading and water deprivation. Since several studies have shown that NO mainly decreases the excitability of OT and VP neurons, NO may function as a local inhibitory feedback on activated SON neurons. In the present study we combined in vivo and in vitro electrophysiological studies to investigate whether NO-induced inhibition of SON neurons is mediated by activation of GABAergic inputs in the SON. In vivo retrodialysis of the NO-donor SNP into the SON inhibited the firing activity of both OT and VP neurons. This inhibition was largely blocked by retrodialysis of the GABA A receptor antagonist bicuculline. In order to understand the cellular mechanisms linking NO and GABAergic systems in the SON, in vitro patch clamp recordings of GABA A synaptic currents were obtained from immunochemically identified neurons in hypothalamic slices. The frequency and amplitude of miniature GABA A synaptic currents in both OT and VP neurons were significantly increased by SNP. These results suggest that NO inhibition of neuronal excitability of OT and VP neurons is largely mediated by pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON. Thus, the proposed NO-GABAergic inhibitory feedback in the SON might constitute an important mechanism by which NO regulates osmotic and fluid balance homeostasis.

scholarly journals What Happens with the Circuit in Alzheimer's Disease in Mice and Humans?

2018 ◽  
Vol 41 (1) ◽  
pp. 277-297 ◽  
Author(s):  
Benedikt Zott ◽  
Marc Aurel Busche ◽  
Reisa A. Sperling ◽  
Arthur Konnerth
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Neuronal Excitability ◽  
Neuronal Damage ◽  
Strong Support ◽  
Underlying Disease ◽  
Electrophysiological Recordings

A major mystery of many types of neurological and psychiatric disorders, such as Alzheimer's disease (AD), remains the underlying, disease-specific neuronal damage. Because of the strong interconnectivity of neurons in the brain, neuronal dysfunction necessarily disrupts neuronal circuits. In this article, we review evidence for the disruption of large-scale networks from imaging studies of humans and relate it to studies of cellular dysfunction in mouse models of AD. The emerging picture is that some forms of early network dysfunctions can be explained by excessively increased levels of neuronal activity. The notion of such neuronal hyperactivity receives strong support from in vivo and in vitro cellular imaging and electrophysiological recordings in the mouse, which provide mechanistic insights underlying the change in neuronal excitability. Overall, some key aspects of AD-related neuronal dysfunctions in humans and mice are strikingly similar and support the continuation of such a translational strategy.

scholarly journals Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

2020 ◽  
Author(s):  
Eduardo Javier Fernandez-Perez ◽  
Braulio Muñoz ◽  
Denisse Andrea Bascuñan ◽  
Christian Peters ◽  
Nicolas Osiel Riffo-Lepe ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Ex Vivo ◽  
Synaptic Activity ◽  
No Production ◽  
Synaptic Currents ◽  
Aβ Oligomers ◽  
Brain Hyperexcitability

Abstract Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro , ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

scholarly journals Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 124
Author(s):  
Ilkka Fagerlund ◽  
Antonios Dougalis ◽  
Anastasia Shakirzyanova ◽  
Mireia Gómez-Budia ◽  
Anssi Pelkonen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Synaptic Activity ◽  
Repetitive Firing ◽  
Electrophysiological Recordings ◽  
Induced Pluripotent ◽  
Neuronal Functions

Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated from induced pluripotent stem cells, migrate to cerebral organoids, and mature into microglia-like cells and interact with synaptic material. Patch-clamp electrophysiological recordings show that the microglia-like population supported the emergence of more mature and diversified neuronal phenotypes displaying repetitive firing of action potentials, low-threshold spikes and synaptic activity, while multielectrode array recordings revealed spontaneous bursting activity and increased power of gamma-band oscillations upon pharmacological challenge with NMDA. To conclude, microglia-like cells within the organoids promote neuronal and network maturation and recapitulate some aspects of microglia-neuron co-development in vivo, indicating that cerebral organoids could be a useful biorealistic human in vitro platform for studying microglia-neuron interactions.

Background Activity Regulates Excitability of Rat Hippocampal CA1 Pyramidal Neurons by Adaptation of a K+ Conductance

2006 ◽  
Vol 95 (3) ◽  
pp. 2007-2012 ◽  
Author(s):  
Ingrid van Welie ◽  
Johannes A. van Hooft ◽  
Wytse J. Wadman
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Dynamic Range ◽  
Background Activity ◽  
Hippocampal Slices ◽  
Synaptic Activity ◽  
Input Output ◽  
Ca1 Pyramidal Neurons

In the in vivo brain background synaptic activity has a strong modulatory influence on neuronal excitability. Here we report that in rat hippocampal slices, blockade of endogenous in vitro background activity results in an increased excitability of CA1 pyramidal neurons within tens of minutes. The increase in excitability constitutes a leftward shift in the input–output relationship of pyramidal neurons, indicating a reduced threshold for the induction of action potentials. The increase in excitability results from an adaptive decrease in a sustained K+ conductance, as recorded from somatic cell–attached patches. After 20 min of blockade of background activity, the mean sustained K+ current amplitude in somatic patches was reduced to 46 ± 9% of that in time-matched control patches. Blockade of background activity did not affect fast Na+ conductance. Together, these results suggests that the reduction in K+ conductance serves as an adaptive mechanism to increase the excitability of CA1 pyramidal neurons in response to changes in background activity such that the dynamic range of the input–output relationship is effectively maintained.

Ketogenic Diet in a Hippocampal Slice

2016 ◽  
Author(s):  
Masahito Kawamura
Keyword(s):  
Ketogenic Diet ◽  
Hippocampal Slice ◽  
Ketone Bodies ◽  
Hippocampal Slices ◽  
Patch Clamp Technique ◽  
Ketogenic Diets ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings

The hippocampus is thought to be a good experimental model for investigating epileptogenesis in and/or antiepileptic therapy for temporal lobe epilepsy. The hippocampus is also a useful target for researching the ketogenic diet. This chapter focuses on electrophysiological recordings using hippocampal slices and introduces their use for studying the anticonvulsant effects underlying ketogenic diets. The major difficulty in using hippocampal slices is the inability to precisely reproduce the in vivo condition of ketogenic diet feeding in this in vitro preparation. Three different approaches are reported to reproduce diet effects in the hippocampal slices: (1) direct application of ketone bodies, (2) mimicking the ketogenic diet condition with whole-cell patch-clamp technique, and (3) hippocampal slices from ketogenic diet–fed animals. Significant results have been found with each of these methods. These three approaches are useful tools to elucidate the underlying anticonvulsant mechanisms of the ketogenic diet.

scholarly journals Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus

2021 ◽  
Vol 22 (24) ◽  
pp. 13604
Author(s):  
Paulina Kazmierska-Grebowska ◽  
Marcin Siwiec ◽  
Joanna Ewa Sowa ◽  
Bartosz Caban ◽  
Tomasz Kowalczyk ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Medial Septum ◽  
Movement Planning ◽  
Theta Oscillations ◽  
Hcn Channels ◽  
Whole Cell Patch Clamp ◽  
Anaesthetized Rats ◽  
Ca1 Pyramidal Neuron

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.

scholarly journals Functional spreading of hyperexcitability induced by human and synthetic intracellular Aβ oligomers

2020 ◽  
Author(s):  
Eduardo J. Fernandez-Perez ◽  
Braulio Muñoz ◽  
Denisse A. Bascuñan ◽  
Christian Peters ◽  
Nicolas O. Riffo-Lepe ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Ex Vivo ◽  
Synaptic Activity ◽  
No Production ◽  
Synaptic Currents ◽  
Aβ Oligomers ◽  
Brain Hyperexcitability

AbstractBackgroundIntracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported.MethodsHere, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro, ex vivo and in vivo.ResultsStarting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties.ConclusionThese results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

scholarly journals Hematopoietic cells maintain hematopoietic fates upon entering the brain

2005 ◽  
Vol 201 (10) ◽  
pp. 1579-1589 ◽  
Author(s):  
Mei Massengale ◽  
Amy J. Wagers ◽  
Hannes Vogel ◽  
Irving L. Weissman
Keyword(s):  
Cell Types ◽  
Neural Cell ◽  
Purkinje Neurons ◽  
Cell Fates ◽  
No Donor ◽  
Hematopoietic Stem ◽  
Lineage Markers ◽  
The Brain

Several studies have reported that bone marrow (BM) cells may give rise to neurons and astrocytes in vitro and in vivo. To further test this hypothesis, we analyzed for incorporation of neural cell types expressing donor markers in normal or injured brains of irradiated mice reconstituted with whole BM or single, purified c-kit+Thy1.1loLin−Sca-1+ (KTLS) hematopoietic stem cells (HSCs), and of unirradiated parabionts with surgically anastomosed vasculature. Each model showed low-level parenchymal engraftment of donor-marker+ cells with 96–100% immunoreactivity for panhematopoietic (CD45) or microglial (Iba1 or Mac1) lineage markers in all cases studied. Other than one arborizing structure in the olfactory bulb of one BM-transplanted animal, possibly representing a neuronal or glial cell process, we found no donor-marker–expressing astrocytes or non-Purkinje neurons among >10,000 donor-marker+ cells from 21 animals. These data strongly suggest that HSCs and their progeny maintain lineage fidelity in the brain and do not adopt neural cell fates with any measurable frequency.

Ultrastructural observations on the in vitro cytoadherence of Plasmodium falciparum infected red blood cells

1990 ◽  
Vol 48 (3) ◽  
pp. 914-915
Author(s):  
D.J.P. Ferguson ◽  
A.R. Berendt ◽  
J. Tansey ◽  
K. Marsh ◽  
C.I. Newbold
Keyword(s):  
Plasmodium Falciparum ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Amelanotic Melanoma ◽  
Cytoplasmic Process ◽  
Umbilical Vein Endothelial Cells

In human malaria, the most serious clinical manifestation is cerebral malaria (CM) due to infection with Plasmodium falciparum. The pathology of CM is thought to relate to the fact that red blood cells containing mature forms of the parasite (PRBC) cytoadhere or sequester to post capillary venules of various tissues including the brain. This in vivo phenomenon has been studied in vitro by examining the cytoadherence of PRBCs to various cell types and purified proteins. To date, three Ijiost receptor molecules have been identified; CD36, ICAM-1 and thrombospondin. The specific changes in the PRBC membrane which mediate cytoadherence are less well understood, but they include the sub-membranous deposition of electron-dense material resulting in surface deformations called knobs. Knobs were thought to be essential for cytoadherence, lput recent work has shown that certain knob-negative (K-) lines can cytoadhere. In the present study, we have used electron microscopy to re-examine the interactions between K+ PRBCs and both C32 amelanotic melanoma cells and human umbilical vein endothelial cells (HUVEC).We confirm previous data demonstrating that C32 cells possess numerous microvilli which adhere to the PRBC, mainly via the knobs (Fig. 1). In contrast, the HUVEC were relatively smooth and the PRBCs appeared partially flattened onto the cell surface (Fig. 2). Furthermore, many of the PRBCs exhibited an invagination of the limiting membrane in the attachment zone, often containing a cytoplasmic process from the endothelial cell (Fig. 2).

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