scholarly journals Elevated serotonergic signaling amplifies synaptic noise and facilitates the emergence of epileptiform network oscillations

2014 ◽  
Vol 112 (10) ◽  
pp. 2357-2373 ◽  
Author(s):  
Pavel A. Puzerey ◽  
Michael J. Decker ◽  
Roberto F. Galán
Keyword(s):  
Computational Model ◽  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Network Activity ◽  
Cortical Dynamics ◽  
Synaptic Excitation ◽  
Network Oscillations ◽  
Synaptic Noise ◽  
Serotonin Signaling

Serotonin fibers densely innervate the cortical sheath to regulate neuronal excitability, but its role in shaping network dynamics remains undetermined. We show that serotonin provides an excitatory tone to cortical neurons in the form of spontaneous synaptic noise through 5-HT3 receptors, which is persistent and can be augmented using fluoxetine, a selective serotonin re-uptake inhibitor. Augmented serotonin signaling also increases cortical network activity by enhancing synaptic excitation through activation of 5-HT2 receptors. This in turn facilitates the emergence of epileptiform network oscillations (10–16 Hz) known as fast runs. A computational model of cortical dynamics demonstrates that these two combined mechanisms, increased background synaptic noise and enhanced synaptic excitation, are sufficient to replicate the emergence fast runs and their statistics. Consistent with these findings, we show that blocking 5-HT2 receptors in vivo significantly raises the threshold for convulsant-induced seizures.

Disruption of Balanced Cortical Excitation and Inhibition by Acoustic Trauma

2008 ◽  
Vol 100 (2) ◽  
pp. 646-656 ◽  
Author(s):  
Ben Scholl ◽  
Michael Wehr
Keyword(s):  
Receptive Field ◽  
Cortical Neurons ◽  
Receptive Fields ◽  
Acoustic Trauma ◽  
Tone Frequency ◽  
Synaptic Excitation ◽  
Before And After ◽  
High Level ◽  
Whole Cell Recordings

Sensory deafferentation results in rapid shifts in the receptive fields of cortical neurons, but the synaptic mechanisms underlying these changes remain unknown. The rapidity of these shifts has led to the suggestion that subthreshold inputs may be unmasked by a selective loss of inhibition. To study this, we used in vivo whole cell recordings to directly measure tone-evoked excitatory and inhibitory synaptic inputs in auditory cortical neurons before and after acoustic trauma. Here we report that acute acoustic trauma disrupted the balance of excitation and inhibition by selectively increasing and reducing the strength of inhibition at different positions within the receptive field. Inhibition was abolished for frequencies far below the trauma-tone frequency but was markedly enhanced near the edges of the region of elevated peripheral threshold. These changes occurred for relatively high-level tones. These changes in inhibition led to an expansion of receptive fields but not by a simple unmasking process. Rather, membrane potential responses were delayed and prolonged throughout the receptive field by distinct interactions between synaptic excitation and inhibition. Far below the trauma-tone frequency, decreased inhibition combined with prolonged excitation led to increased responses. Near the edges of the region of elevated peripheral threshold, increased inhibition served to delay rather than abolish responses, which were driven by prolonged excitation. These results show that the rapid receptive field shifts caused by acoustic trauma are caused by distinct mechanisms at different positions within the receptive field, which depend on differential disruption of excitation and inhibition.

scholarly journals Network activity influences the subthreshold and spiking visual responses of pyramidal neurons in a three-layer cortex

2016 ◽  
Author(s):  
Nathaniel C. Wright ◽  
Ralf Wessel
Keyword(s):  
Membrane Potential ◽  
Cortical Neurons ◽  
Visual Stimulation ◽  
Ex Vivo ◽  
Network Activity ◽  
Visual Responses ◽  
Cortical Function ◽  
Sensory Evoked ◽  
High Conductance

A primary goal of systems neuroscience is to understand cortical function, which typically involves studying spontaneous and sensory-evoked cortical activity. Mounting evidence suggests a strong and complex relationship between the ongoing and evoked state. To date, most work in this area has been based on spiking in populations of neurons. While advantageous in many respects, this approach is limited in scope; it records the activities of a minority of neurons, and gives no direct indication of the underlying subthreshold dynamics. Membrane potential recordings can fill these gaps in our understanding, but are difficult to obtain in vivo. Here, we record subthreshold cortical visual responses in the ex vivo turtle eye-attached whole-brain preparation, which is ideally-suited to such a study. In the absence of visual stimulation, the network is “synchronous”; neurons display network-mediated transitions between low- and high-conductance membrane potential states. The prevalence of these slow-wave transitions varies across turtles and recording sessions. Visual stimulation evokes similar high-conductance states, which are on average larger and less reliable when the ongoing state is more synchronous. Responses are muted when immediately preceded by large, spontaneous high-conductance events. Evoked spiking is sparse, highly variable across trials, and mediated by concerted synaptic inputs that are in general only very weakly correlated with inputs to nearby neurons. Together, these results highlight the multiplexed influence of the cortical network on the spontaneous and sensory-evoked activity of individual cortical neurons.

scholarly journals KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition

2018 ◽  
Author(s):  
Vincent Magloire ◽  
Jonathan Cornford ◽  
Andreas Lieb ◽  
Dimitri M. Kullmann ◽  
Ivan Pavlov
Keyword(s):  
Potassium Chloride ◽  
Cortical Neurons ◽  
Closed Loop ◽  
Network Activity ◽  
Intracellular Chloride ◽  
Cortical Interneurons ◽  
The Face ◽  
Somatic Inhibition

AbstractAlthough cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of parvalbumin-positive perisomatic-targeting (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain intracellular chloride levels in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.

scholarly journals Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy

2016 ◽  
Vol 26 (4) ◽  
pp. 1778-1794 ◽  
Author(s):  
Angela Michela De Stasi ◽  
Pasqualina Farisello ◽  
Iacopo Marcon ◽  
Stefano Cavallari ◽  
Angelo Forli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Myoclonic Epilepsy ◽  
Network Activity ◽  
Cortical Dynamics ◽  
Severe Myoclonic Epilepsy ◽  
Myoclonic Epilepsy Of Infancy

scholarly journals Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

2020 ◽  
Author(s):  
Javier Zorrilla de San Martin ◽  
Cristina Donato ◽  
Jérémy Peixoto ◽  
Andrea Aguirre ◽  
Vikash Choudhary ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Prefrontal Cortex ◽  
Cognitive Deficits ◽  
Pyramidal Neurons ◽  
Phase Locking ◽  
Network Activity ◽  
Inhibitory Circuits ◽  
Network Oscillations ◽  
Fast Spiking

AbstractDown syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

Disruption of GABAA Receptors on GABAergic Interneurons Leads to Increased Oscillatory Power in the Olfactory Bulb Network

2001 ◽  
Vol 86 (6) ◽  
pp. 2823-2833 ◽  
Author(s):  
Zoltan Nusser ◽  
Leslie M. Kay ◽  
Gilles Laurent ◽  
Gregg E. Homanics ◽  
Istvan Mody
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Fold Increase ◽  
Network Activity ◽  
Gabaergic Interneurons ◽  
Synaptic Inhibition ◽  
Principal Cells ◽  
Network Oscillations

Synchronized neural activity is believed to be essential for many CNS functions, including neuronal development, sensory perception, and memory formation. In several brain areas GABAA receptor–mediated synaptic inhibition is thought to be important for the generation of synchronous network activity. We have used GABAA receptor β3 subunit deficient mice (β3−/−) to study the role of GABAergic inhibition in the generation of network oscillations in the olfactory bulb (OB) and to reveal the role of such oscillations in olfaction. The expression of functional GABAA receptors was drastically reduced (>93%) in β3−/− granule cells, the local inhibitory interneurons of the OB. This was revealed by a large reduction of muscimol-evoked whole-cell current and the total current mediated by spontaneous, miniature inhibitory postsynaptic currents (mIPSCs). In β3−/− mitral/tufted cells (principal cells), there was a two-fold increase in mIPSC amplitudes without any significant change in their kinetics or frequency. In parallel with the altered inhibition, there was a significant increase in the amplitude of theta (80% increase) and gamma (178% increase) frequency oscillations in β3−/− OBs recorded in vivo from freely moving mice. In odor discrimination tests, we found β3−/− mice to be initially the same as, but better with experience than β3+/+ mice in distinguishing closely related monomolecular alcohols. However, β3−/− mice were initially better and then worse with practice than control mice in distinguishing closely related mixtures of alcohols. Our results indicate that the disruption of GABAAreceptor–mediated synaptic inhibition of GABAergic interneurons and the augmentation of IPSCs in principal cells result in increased network oscillations in the OB with complex effects on olfactory discrimination, which can be explained by an increase in the size or effective power of oscillating neural cell assemblies among the mitral cells of β3−/− mice.

Enhancement of Visual Responsiveness by Spontaneous Local Network Activity In Vivo

2007 ◽  
Vol 97 (6) ◽  
pp. 4186-4202 ◽  
Author(s):  
Bilal Haider ◽  
Alvaro Duque ◽  
Andrea R. Hasenstaub ◽  
Yuguo Yu ◽  
David A. McCormick
Keyword(s):  
Cortical Neurons ◽  
Extracellular Recording ◽  
Spike Timing ◽  
Network Activity ◽  
Local Network ◽  
Sensory Responses ◽  
Simple And Complex Cells ◽  
Local Circuits ◽  
Neocortical Network

Spontaneous activity within local circuits affects the integrative properties of neurons and networks. We have previously shown that neocortical network activity exhibits a balance between excitatory and inhibitory synaptic potentials, and such activity has significant effects on synaptic transmission, action potential generation, and spike timing. However, whether such activity facilitates or reduces sensory responses has yet to be clearly determined. We examined this hypothesis in the primary visual cortex in vivo during slow oscillations in ketamine-xylazine anesthetized cats. We measured network activity (Up states) with extracellular recording, while simultaneously recording postsynaptic potentials (PSPs) and action potentials in nearby cells. Stimulating the receptive field revealed that spiking responses of both simple and complex cells were significantly enhanced (>2-fold) during network activity, as were spiking responses to intracellular injection of varying amplitude artificial conductance stimuli. Visually evoked PSPs were not significantly different in amplitude during network activity or quiescence; instead, spontaneous depolarization caused by network activity brought these evoked PSPs closer to firing threshold. Further examination revealed that visual responsiveness was gradually enhanced by progressive membrane potential depolarization. These spontaneous depolarizations enhanced responsiveness to stimuli of varying contrasts, resulting in an upward (multiplicative) scaling of the contrast response function. Our results suggest that small increases in ongoing balanced network activity that result in depolarization may provide a rapid and generalized mechanism to control the responsiveness (gain) of cortical neurons, such as occurs during shifts in spatial attention.

scholarly journals Stretch injury selectively enhances extrasynaptic, GluN2B-containing NMDA receptor function in cortical neurons

2013 ◽  
Vol 110 (1) ◽  
pp. 131-140 ◽  
Author(s):  
Carrie R. Ferrario ◽  
Blaise O. Ndukwe ◽  
Jianhua Ren ◽  
Leslie S. Satin ◽  
Paulette B. Goforth
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Ampa Receptor ◽  
Cortical Neurons ◽  
Mechanical Stretch ◽  
Receptor Activity ◽  
Network Activity ◽  
Stretch Injury

Alterations in the function and expression of NMDA receptors are observed after in vivo and in vitro traumatic brain injury. We recently reported that mechanical stretch injury in cortical neurons transiently increases the contribution of NMDA receptors to network activity and results in an increase in calcium-permeable AMPA (CP-AMPA) receptor-mediated transmission 4 h postinjury ( Goforth et al. 2011 ). Here, we evaluated changes in the function of synaptic vs. extrasynaptic GluN2B-containing NMDA receptors after injury. We also determined whether postinjury treatment with the GluN2B-selective antagonist Ro 25-6981 or memantine prevents injury-induced increases in CP-AMPA receptor activity. We found that injury increased extrasynaptic, GluN2B-containing NMDA receptor-mediated whole cell currents. In contrast, we found no differences in synaptic NMDA receptor-mediated transmission after injury. Furthermore, treatment with Ro 25-6981 or memantine after injury prevented injury-induced increases in CP-AMPA receptor-mediated activity. Together, our data suggest that increased NMDA receptor activity after injury is predominantly due to alterations in extrasynaptic, GluN2B-containing NMDA receptors and that activation of these receptors may contribute to the appearance of CP-AMPA receptors after injury.

scholarly journals Chronic lithium treatment alters the excitatory/inhibitory balance of synaptic networks and reduces mGluR5-PKC signaling

2020 ◽  
Author(s):  
A. Khayachi ◽  
A. R. Ase ◽  
C. Liao ◽  
A. Kamesh ◽  
N. Kuhlmann ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Excitability ◽  
Lithium Treatment ◽  
Mood Stabilizer ◽  
Network Activity ◽  
Calcium Flux ◽  
Efficient Treatment ◽  
Therapeutic Benefits ◽  
Underlying Mechanisms ◽  
Depressive Episodes

ABSTRACTBipolar disorder (BD) is characterized by cyclical alternations between mania and depression, often comorbid with psychosis, and suicide. The mood stabilizer lithium, compared to other medications, is the most efficient treatment for prevention of manic and depressive episodes. The pathophysiology of BD, and lithium’s mode of action, are yet to be fully understood. Evidence suggests a change in the balance of excitatory/inhibitory activity, favouring excitation in BD. Here, we sought to establish a holistic appreciation of the neuronal consequences of lithium exposure in mouse cortical neurons and identify underlying mechanisms. We found that chronic (but not acute) lithium treatment significantly reduced intracellular calcium flux, specifically through the activation of the metabotropic glutamatergic receptor mGluR5. This was associated with altered phosphorylation of PKC and GSK3 kinases, reduced neuronal excitability, and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory/inhibitory balance in the network toward inhibition. Together, the results revealed how lithium dampens neuronal excitability and glutamatergic network activity, which are predicted to be overactive in the manic phase of BD. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium, but with reduced toxicity.

scholarly journals Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis

2018 ◽  
Author(s):  
Sashaina Fanibunda ◽  
Sukrita Deb ◽  
Babukrishna Maniyadath ◽  
Samir Gupta ◽  
Noelia Weisstaub ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Cortical Neurons ◽  
Neuronal Excitability ◽  
In Vivo Studies ◽  
Primary Role ◽  
Dependent Manner ◽  
Atp Levels ◽  
And Function ◽  
Neuroprotective Action

Mitochondria in neurons in addition to their primary role in bioenergetics also contribute to specialized functions including regulation of synaptic transmission, Ca2+ homeostasis, neuronal excitability and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial genes. This was accompanied by increased cellular ATP levels, basal and maximal respiration, as well as spare respiratory capacity. Mechanistically the effects of 5-HT were mediated via the 5-HT2A receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT2A receptor stimulation increased cortical mtDNA and ATP levels, in a SIRT1 dependent manner. In cortical neurons, 5-HT enhanced expression of anti-oxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as a novel upstream regulator of mitochondrial biogenesis and function in cortical neurons, and implicate the mitochondrial effects of 5-HT in its neuroprotective action.

Sign in / Sign up

Export Citation Format

Share Document