scholarly journals Vasopressin acts as a synapse organizer in limbic regions by boosting PSD95 and GluA1 expression

2020 ◽  
Author(s):  
Limei Zhang ◽  
Teresa Padilla-Flores ◽  
Vito S. Hernández ◽  
Elba Campos-Lira ◽  
Mario A. Zetter ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Synaptic Proteins ◽  
Scaffolding Protein ◽  
Synaptic Organization ◽  
Limbic Regions

AbstractHypothalamic arginine vasopressin (AVP)-containing magnocellular neurosecretory neurons (AVPMNN) emit collaterals to synaptically innervate limbic regions influencing learning, motivational behavior and fear responses. The purpose of the present work is to characterize the dynamics of expression changes of two postsynaptic density (PSD) proteins, AMPAR subunit GluA1 and PSD scaffolding protein 95 (PSD95), which are known to be key determinants for synaptic strength, in response to in vivo and ex vivo manipulations of AVPMNN neuronal activation state, or exposure to exogenous AVP, metabolites and some signaling pathway inhibitors. Both long term water deprivation in vivo, which powerfully upregulates AVPMNN activity, and exogenous APV application ex vivo in brain slices, increased GluA1 and PSD95 expression and enhanced neuronal excitability in ventral hippocampal CA1 pyramidal neurons. Involvement of PI3k signaling in AVP-dependent plasticity is suggested by blockade of both AVP-induced protein up-regulation and enhanced neuronal excitability by the PI3k blocker wortmannin in hippocampal slices. We interpret these results as part of vasopressin’s central effects on synaptic organization in limbic regions modulating the strength of a specific set of synaptic proteins in hypothalamic-limbic circuits.Supported by grantsUNAM-DGAPA-PAPIIT-IN216918 & CONACYT-CB-238744.

scholarly journals Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy

2021 ◽  
Vol 14 ◽  
Author(s):  
Achira Roy ◽  
Victor Z. Han ◽  
Angela M. Bard ◽  
Devin T. Wehle ◽  
Stephen E. P. Smith ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Genetic Model ◽  
Ex Vivo ◽  
Significant Proportion ◽  
Intractable Epilepsy ◽  
Therapeutic Interventions ◽  
Hippocampal Pyramidal Neurons ◽  
Phosphoinositide 3 Kinase

Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA, encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo, we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.

scholarly journals Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology and Hebbian plasticity in the mouse hippocampus

2018 ◽  
Author(s):  
Thiago C. Moulin ◽  
Lyvia L. Petiz ◽  
Danielle Rayêe ◽  
Jessica Winne ◽  
Roberto G. Maia ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Spine Density ◽  
Optogenetic Stimulation ◽  
Light Pulses ◽  
Ca1 Region ◽  
Hebbian Plasticity

AbstractProlonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

scholarly journals Impaired state-dependent potentiation of GABAergic synaptic currents triggers seizures in an idiopathic generalized epilepsy model

2020 ◽  
Author(s):  
Chun-Qing Zhang ◽  
Mackenzie A. Catron ◽  
Li Ding ◽  
Caitlyn M. Hanna ◽  
Martin J. Gallagher ◽  
...  
Keyword(s):  
Slow Wave ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Slow Wave Sleep ◽  
Ex Vivo ◽  
Brain Slices ◽  
Idiopathic Generalized Epilepsy ◽  
Synaptic Currents ◽  
Generalized Epilepsy

AbstractIdiopathic generalized epilepsy(IGE) patients have genetic causes and their seizure onset mechanisms particularly during sleep remain elusive. Here we proposed that sleep-like slow-wave oscillations(0.5 Hz SWOs) potentiated excitatory or inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type(wt) mouse ex vivo brain slices. In contrast, SWOs potentiated excitatory, not inhibitory, currents in cortical neurons from heterozygous(het) knock-in(KI) IGE mice(GABAA receptor γ2 subunit Gabrg2Q390X mutation), creating an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potentials. Similarly, more physiologically similar up/down-state(present during slow-wave sleep) induction in cortical neurons could potentiate excitatory synaptic currents within slices from wt/het Gabrg2Q390X KI mice. Consequently, SWOs or up/down-state induction in vivo (using optogenetic method) could trigger epileptic spike-wave discharges(SWDs) in het Gabrg2Q390X KI mice. To our knowledge, this is the first operative mechanism to explain why epileptic SWDs preferentially happen during non-REM sleep or quiet-wakefulness in human IGE patients.

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.

scholarly journals Intrinsic excitability mechanisms of neuronal ensemble formation

2020 ◽  
Author(s):  
Tzitzitlini Alejandre-García ◽  
Samuel Kim ◽  
Jesús Pérez-Ortega ◽  
Rafael Yuste
Keyword(s):  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Cell Voltage ◽  
Membrane Resistance ◽  
Neuronal Ensembles ◽  
Neuronal Ensemble ◽  
Evoked Activity

AbstractNeuronal ensembles are coactive groups of cortical neurons, found in both spontaneous and evoked activity, which can mediate perception and behavior (Cossart et al., 2003; Buzsáki, 2010; Carrillo-Reid et al., 2019; Marshel et al., 2019). To understand the mechanism that lead to the formation of neuronal ensembles, we generated optogenetically artificial photo-ensembles in layer 2/3 pyramidal neurons in brain slices of mouse visual cortex from both sexes, replicating an optogenetic protocol to generate ensembles in vivo by simultaneous coactivation of neurons (Carrillo-Reid et al. 2016). Using whole-cell voltage-clamp recordings from individual neurons and connected pairs, we find that synaptic properties of photostimulated were surprisingly unaffected, without any signs of Hebbian plasticity. However, extracellular recordings revealed that photostimulation induced strong increases in spontaneous action potential activity. Using perforated patch clamp recordings, we find increases in neuronal excitability, accompanied by increases in membrane resistance and a reduction in spike threshold. We conclude that the formation of neuronal ensemble by photostimulation is mediated by cell-intrinsic changes in excitability, rather than by Hebbian synaptic plasticity or changes in local synaptic connectivity. We propose an “iceberg” model, by which increased neuronal excitability makes subthreshold connections become suprathreshold, increasing the functional effect of already existing synapses and generating a new neuronal ensemble.

scholarly journals Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomersin vivo

2018 ◽  
Author(s):  
Hyowon Chung ◽  
Kyerl Park ◽  
Hyun Jae Jang ◽  
Michael M Kohl ◽  
Jeehyun Kwag
Keyword(s):  
Learning And Memory ◽  
Peak Power ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Theta Oscillations ◽  
Ca1 Pyramidal Neurons ◽  
Theta Frequency ◽  
Hippocampal Theta

AbstractAbnormal accumulation of amyloid β oligomers (AβO) is a hallmark of Alzheimer’s disease (AD), which leads to learning and memory deficits. Hippocampal theta oscillations that are critical in spatial navigation, learning and memory are impaired in AD. Since GABAergic interneurons, such as somatostatin-positive (SST+) and parvalbumin-positive (PV+) interneurons, are believed to play key roles in the hippocampal oscillogenesis, we asked whether AβO selectively impairs these SST+ and PV+ interneurons. To selectively manipulate SST+ or PV+ interneuron activity in mice with AβO pathologyin vivo, we co-injected AβO and adeno-associated virus (AAV) for expressing floxed channelrhodopsin-2 (ChR2) into the hippocampus of SST-Cre or PV-Cre mice. Local field potential (LFP) recordingsin vivoin these AβO–injected mice showed a reduction in the peak power of theta oscillations and desynchronization of spikes from CA1 pyramidal neurons relative to theta oscillations compared to those in control mice. Optogenetic-activation of SST+ but not PV+ interneurons in AβO–injected mice fully restored the peak power of theta oscillations and resynchronized the theta spike phases to a level observed in control mice.In vitrowhole-cell voltage-clamp recordings in CA1 pyramidal neurons in hippocampal slices treated with AβO revealed that short-term plasticity of SST+ interneuron inhibitory inputs to CA1 pyramidal neurons at theta frequency were selectively disrupted while that of PV+ interneuron inputs were unaffected. Together, our results suggest that dysfunction in inputs from SST+ interneurons to CA1 pyramidal neurons may underlie the impairment of theta oscillations observed in AβO-injected micein vivo.Our findings identify SST+ interneurons as a target for restoring theta-frequency oscillations in early AD.

scholarly journals Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations

2019 ◽  
Vol 130 (6) ◽  
pp. 1049-1063 ◽  
Author(s):  
Logan J. Voss ◽  
Paul S. García ◽  
Harald Hentschke ◽  
Matthew I. Banks
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Regions ◽  
Cortical Network ◽  
Network Activity ◽  
Common Mechanism ◽  
General Anesthetics ◽  
Neural Basis

Abstract General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine and safe, there are many vagaries that remain unexplained. In this paper, the authors review the evidence that cortical network activity is particularly sensitive to general anesthetics, and suggest that disruption to communication in, and/or among, cortical brain regions is a common mechanism of anesthesia that ultimately produces loss of consciousness. The authors review data from acute brain slices and organotypic cultures showing that anesthetics with differing molecular mechanisms of action share in common the ability to impair neurophysiologic communication. While many questions remain, together, ex vivo and in vivo investigations suggest that a unified understanding of both clinical anesthesia and the neural basis of consciousness is attainable.

scholarly journals Ginkgo Extract EGb761 Confers Neuroprotection by Reduction of Glutamate Release in Ischemic Brain

2012 ◽  
Vol 15 (1) ◽  
pp. 94 ◽  
Author(s):  
Alexander Mdzinarishvili ◽  
Rachita K. Sambria ◽  
Dorothee Lang ◽  
Jochen Klein
Keyword(s):  
Glutamate Release ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Cell Swelling ◽  
Experimental Stroke ◽  
Cell Degeneration ◽  
Edema Formation ◽  
Ginkgo Extract

Purpose - Ginkgo extract EGb761 has shown anti-edema and anti-ischemic effects in various experimental models. In the present study, we demonstrate neuroprotective effects of EGb761 in experimental stroke while monitoring brain metabolism by microdialysis. Methods - We have used oxygen-glucose deprivation in brain slices in vitro and middle cerebral artery occlusion (MCAO) in vivo to induce ischemia in mouse brain. We used microdialysis in mouse striatum to monitor extracellular concentrations of glucose and glutamate. Results - In vitro, EGb761 reduced ischemia-induced cell swelling in hippocampal slices by 60%. In vivo, administration of EGb761 (300 mg/kg) reduced cell degeneration and edema formation after MCAO by 35-50%. Immediately following MCAO, striatal glucose levels dropped to 25% of controls, and this reduction was not significantly affected by EGb761. Striatal glutamate levels, in contrast, increased 15-fold after MCAO; after pretreatment with EGb761, glutamate levels only increased by 4-5fold. Conclusions - We show that pretreatment with EGb761 strongly reduces cellular edema formation and neurodegeneration under conditions of ischemia. The mechanism of action seems to be related to a reduction of excitotoxicity, because ischemia-induced release of glutamate was strongly suppressed. Ginkgo extracts such as EGb761 may be valuable to prevent ischemia-induced damage in stroke-prone patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Effects of CYP46A1 Inhibition on Long-Term-Depression in Hippocampal Slices ex vivo and 24S-Hydroxycholesterol Levels in Mice in vivo

2020 ◽  
Vol 13 ◽  
Author(s):  
Michael Popiolek ◽  
Yukitoshi Izumi ◽  
Allen T. Hopper ◽  
Jing Dai ◽  
Silke Miller ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Hippocampal Slices ◽  
Long Term Depression

scholarly journals Brain metabolism modulates neuronal excitability in a mouse model of pyruvate dehydrogenase deficiency

2019 ◽  
Vol 11 (480) ◽  
pp. eaan0457 ◽  
Author(s):  
Vikram Jakkamsetti ◽  
Isaac Marin-Valencia ◽  
Qian Ma ◽  
Levi B. Good ◽  
Tyler Terrill ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Brain Metabolism ◽  
Neuronal Excitability ◽  
Oscillation Amplitude ◽  
Brain Slices ◽  
Tca Cycle ◽  
Gamma Oscillations ◽  
Epileptiform Discharges ◽  
Discharge Duration

Glucose is the ultimate substrate for most brain activities that use carbon, including synthesis of the neurotransmitters glutamate and γ-aminobutyric acid via mitochondrial tricarboxylic acid (TCA) cycle. Brain metabolism and neuronal excitability are thus interdependent. However, the principles that govern their relationship are not always intuitive because heritable defects of brain glucose metabolism are associated with the paradoxical coexistence, in the same individual, of episodic neuronal hyperexcitation (seizures) with reduced basal cerebral electrical activity. One such prototypic disorder is pyruvate dehydrogenase (PDH) deficiency (PDHD). PDH is central to metabolism because it steers most of the glucose-derived flux into the TCA cycle. To better understand the pathophysiology of PDHD, we generated mice with brain-specific reduced PDH activity that paralleled salient human disease features, including cerebral hypotrophy, decreased amplitude electroencephalogram (EEG), and epilepsy. The mice exhibited reductions in cerebral TCA cycle flux, glutamate content, spontaneous, and electrically evoked in vivo cortical field potentials and gamma EEG oscillation amplitude. Episodic decreases in gamma oscillations preceded most epileptiform discharges, facilitating their prediction. Fast-spiking neuron excitability was decreased in brain slices, contributing to in vivo action potential burst prolongation after whisker pad stimulation. These features were partially reversed after systemic administration of acetate, which augmented cerebral TCA cycle flux, glutamate-dependent synaptic transmission, inhibition and gamma oscillations, and reduced epileptiform discharge duration. Thus, our results suggest that dysfunctional excitability in PDHD is consequent to reduced oxidative flux, which leads to decreased neuronal activation and impaired inhibition, and can be mitigated by an alternative metabolic substrate.

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