scholarly journals Retrosplenial Cortex Contributes to Network Changes during Seizures in the GAERS Absence Epilepsy Rat Model

2021 ◽  
Author(s):  
Lydia Wachsmuth ◽  
Maia Datunashvili ◽  
Katharina Kemper ◽  
Franziska Albers ◽  
Henriette Lambers ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Local Level ◽  
Small World ◽  
Resting State Fmri ◽  
Absence Epilepsy ◽  
Retrosplenial Cortex ◽  
Synaptic Activity ◽  
Brain State ◽  
Cortical Regions

Abstract Resting state-fMRI (rs-fMRI) was performed to explore brain networks in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and in non-epileptic controls (NEC) during monitoring of the brain state by simultaneous optical Ca2+-recordings. Graph theoretical analysis allowed for identification of acute and chronic network changes and revealed preserved small world topology before and after seizure onset. The most prominent acute change in network organization during seizures was the segregation of cortical regions from the remaining brain. Stronger connections between thalamic with limbic regions compared to pre-seizure state indicated network regularization during seizures. When comparing between strains, intra-thalamic connections were prominent in NEC, on local level represented by higher thalamic strengths and hub scores. Subtle differences were observed for retrosplenial cortex (RS), forming more connections beyond cortex in epileptic rats, and showing a tendency to lateralization during seizures. A potential role of RS as hub between subcortical and cortical regions in epilepsy was supported by increased numbers of parvalbumin-positive (PV+) interneurons together with enhanced inhibitory synaptic activity and neuronal excitability in pyramidal neurons. By combining multimodal fMRI data, graph theoretical methods, and electrophysiological recordings we identified the RS as promising target for modulation of seizure activity and/or comorbidities.

scholarly journals Induction of an Isoelectric Brain State to Investigate the Impact of Endogenous Synaptic Activity on Neuronal Excitability In Vivo

10.3791/53576 ◽  
2016 ◽  
Author(s):  
Tristan Altwegg-Boussac ◽  
Séverine Mahon ◽  
Mario Chavez ◽  
Stéphane Charpier ◽  
Adrien E. Schramm
Keyword(s):  
Neuronal Excitability ◽  
Synaptic Activity ◽  
Brain State ◽  
The Impact

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia

2014 ◽  
Vol 111 (6) ◽  
pp. 1227-1237 ◽  
Author(s):  
Fu-Wen Zhou ◽  
Steven N. Roper
Keyword(s):  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Receptor Potential ◽  
Synaptic Activity ◽  
Bath Application ◽  
Enhanced Expression ◽  
Transient Receptor ◽  
Canonical Type

Neuronal hyperexcitability plays an important role in epileptogenesis. Conditions of low extracellular calcium (Ca) or magnesium (Mg) can induce hyperexcitability and epileptiform activity with unclear mechanisms. Transient receptor potential canonical type 3 (TRPC3) channels play a pivotal role in neuronal excitability and are activated in low-Ca and/or low-Mg conditions to depolarize neurons. TRPC3 staining was highly enriched in immature, but very weak in mature, control cortex, whereas it was strong in dysplastic cortex at all ages. Depolarization and susceptibility to epileptiform activity increased with decreasing Ca and Mg. Combinations of low Ca and low Mg induced larger depolarization in pyramidal neurons and greater susceptibility to epileptiform activity in immature and dysplastic cortex than in mature and control cortex, respectively. Intracellular application of anti-TRPC3 antibody to block TRPC3 channels and bath application of the selective TRPC3 inhibitor Pyr3 greatly diminished depolarization in immature control and both immature and mature dysplastic cortex with strong TRPC3 expression. Epileptiform activity was initiated in low Ca and low Mg when synaptic activity was blocked, and Pyr3 completely suppressed this activity. In conclusion, TRPC3 primarily mediates low Ca- and low Mg-induced depolarization and epileptiform activity, and the enhanced expression of TRPC3 could make dysplastic and immature cortex more hyperexcitable and more susceptible to epileptiform activity.

scholarly journals Kv1.1 channels mediate network excitability and feed-forward inhibition in local amygdala circuits

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samrat Thouta ◽  
Yiming Zhang ◽  
Esperanza Garcia ◽  
Terrance P. Snutch
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Brain Regions ◽  
Spike Timing ◽  
Synaptic Activity ◽  
Unexpected Death ◽  
Feed Forward ◽  
Spontaneous Seizures ◽  
Feed Forward Inhibition

AbstractKv1.1 containing potassium channels play crucial roles towards dampening neuronal excitability. Mice lacking Kv1.1 subunits (Kcna1−/−) display recurrent spontaneous seizures and often exhibit sudden unexpected death. Seizures in Kcna1−/− mice resemble those in well-characterized models of temporal lobe epilepsy known to involve limbic brain regions and spontaneous seizures result in enhanced cFos expression and neuronal death in the amygdala. Yet, the functional alterations leading to amygdala hyperexcitability have not been identified. In this study, we used Kcna1−/− mice to examine the contributions of Kv1.1 subunits to excitability in neuronal subtypes from basolateral (BLA) and central lateral (CeL) amygdala known to exhibit distinct firing patterns. We also analyzed synaptic transmission properties in an amygdala local circuit predicted to be involved in epilepsy-related comorbidities. Our data implicate Kv1.1 subunits in controlling spontaneous excitatory synaptic activity in BLA pyramidal neurons. In the CeL, Kv1.1 loss enhances intrinsic excitability and impairs inhibitory synaptic transmission, notably resulting in dysfunction of feed-forward inhibition, a critical mechanism for controlling spike timing. Overall, we find inhibitory control of CeL interneurons is reduced in Kcna1−/− mice suggesting that basal inhibitory network functioning is less able to prevent recurrent hyperexcitation related to seizures.

Synaptic Regulation of the Slow Ca2+-Activated K+ Current in Hippocampal CA1 Pyramidal Neurons: Implication in Epileptogenesis

2001 ◽  
Vol 86 (6) ◽  
pp. 2878-2886 ◽  
Author(s):  
Eduardo D. Martín ◽  
Alfonso Araque ◽  
Washington Buño
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Epileptiform Activity ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Synaptic Activity ◽  
Cooperative Action ◽  
Epileptiform Discharges ◽  
Group I

The slow Ca2+-activated K+ current (sIAHP) plays a critical role in regulating neuronal excitability, but its modulation during abnormal bursting activity, as in epilepsy, is unknown. Because synaptic transmission is enhanced during epilepsy, we investigated the synaptically mediated regulation of the sIAHP and its control of neuronal excitability during epileptiform activity induced by 4-aminopyridine (4AP) or 4AP+Mg2+-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca2+ techniques to analyze the sIAHP modifications that parallel epileptiform activity. Epileptiform activity was characterized by slow, repetitive, spontaneous depolarizations and action potential bursts and was associated with increased frequency and amplitude of spontaneous excitatory postsynaptic currents and a reduced sIAHP. The metabotropic glutamate receptor (mGluR) antagonist (S)-α-methyl-4-carboxyphenylglycine did not modify synaptic activity enhancement but did prevent sIAHP inhibition and epileptiform discharges. The mGluR-dependent regulation of the sIAHP was not caused by modulated intracellular Ca2+ signaling. Histamine, isoproterenol, and (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid reduced the sIAHP but did not increase synaptic activity and failed to evoke epileptiform activity. We conclude that 4AP or 4AP+Mg-free–induced enhancement of synaptic activity reduced the sIAHP via activation of postsynaptic group I/II mGluRs. The increased excitability caused by the lack of negative feedback provided by the sIAHP contributes to epileptiform activity, which requires the cooperative action of increased synaptic activity.

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.

Dopamine Increases the Gain of the Input-Output Response of Rat Prefrontal Pyramidal Neurons

2008 ◽  
Vol 99 (6) ◽  
pp. 2985-2997 ◽  
Author(s):  
Kay Thurley ◽  
Walter Senn ◽  
Hans-Rudolf Lüscher
Keyword(s):  
Working Memory ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
D1 Receptors ◽  
Input Output ◽  
Prefrontal Cortical ◽  
Noisy Input ◽  
Relationship Of

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

Dichotomy of Action-Potential Backpropagation in CA1 Pyramidal Neuron Dendrites

2001 ◽  
Vol 86 (6) ◽  
pp. 2998-3010 ◽  
Author(s):  
Nace L. Golding ◽  
William L. Kath ◽  
Nelson Spruston
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Resting Potential ◽  
Model Parameters ◽  
Voltage Sensitivity ◽  
Whole Cell ◽  
Ca1 Pyramidal Neurons ◽  
Whole Cell Recordings

In hippocampal CA1 pyramidal neurons, action potentials are typically initiated in the axon and backpropagate into the dendrites, shaping the integration of synaptic activity and influencing the induction of synaptic plasticity. Despite previous reports describing action-potential propagation in the proximal apical dendrites, the extent to which action potentials invade the distal dendrites of CA1 pyramidal neurons remains controversial. Using paired somatic and dendritic whole cell recordings, we find that in the dendrites proximal to 280 μm from the soma, single backpropagating action potentials exhibit <50% attenuation from their amplitude in the soma. However, in dendritic recordings distal to 300 μm from the soma, action potentials in most cells backpropagated either strongly (26–42% attenuation; n = 9/20) or weakly (71–87% attenuation; n = 10/20) with only one cell exhibiting an intermediate value (45% attenuation). In experiments combining dual somatic and dendritic whole cell recordings with calcium imaging, the amount of calcium influx triggered by backpropagating action potentials was correlated with the extent of action-potential invasion of the distal dendrites. Quantitative morphometric analyses revealed that the dichotomy in action-potential backpropagation occurred in the presence of only subtle differences in either the diameter of the primary apical dendrite or branching pattern. In addition, action-potential backpropagation was not dependent on a number of electrophysiological parameters (input resistance, resting potential, voltage sensitivity of dendritic spike amplitude). There was, however, a striking correlation of the shape of the action potential at the soma with its amplitude in the dendrite; larger, faster-rising, and narrower somatic action potentials exhibited more attenuation in the distal dendrites (300–410 μm from the soma). Simple compartmental models of CA1 pyramidal neurons revealed that a dichotomy in action-potential backpropagation could be generated in response to subtle manipulations of the distribution of either sodium or potassium channels in the dendrites. Backpropagation efficacy could also be influenced by local alterations in dendritic side branches, but these effects were highly sensitive to model parameters. Based on these findings, we hypothesize that the observed dichotomy in dendritic action-potential amplitude is conferred primarily by differences in the distribution, density, or modulatory state of voltage-gated channels along the somatodendritic axis.

scholarly journals Neural differentiation is moderated by age in scene- but not face-selective cortical regions

2020 ◽  
Author(s):  
Sabina Srokova ◽  
Paul F. Hill ◽  
Joshua D. Koen ◽  
Danielle R. King ◽  
Michael D. Rugg
Keyword(s):  
Cognitive Aging ◽  
Neural Differentiation ◽  
Memory Performance ◽  
Retrosplenial Cortex ◽  
Stimulus Category ◽  
Age Related ◽  
Pattern Similarity ◽  
Cortical Regions ◽  
Neural Selectivity ◽  
Parahippocampal Place Area

AbstractThe aging brain is characterized by neural dedifferentiation – an apparent decrease in the functional selectivity of category-selective cortical regions. Age-related reductions in neural differentiation have been proposed to play a causal role in cognitive aging. Recent findings suggest, however, that age-related dedifferentiation is not equally evident for all stimulus categories and, additionally, that the relationship between neural differentiation and cognitive performance is not moderated by age. In light of these findings, in the present experiment younger and older human adults (males and females) underwent fMRI as they studied words paired with images of scenes or faces prior to a subsequent memory task. Neural selectivity was measured in two scene-selective (parahippocampal place area and retrosplenial cortex) and two face-selective (fusiform and occipital face areas) regions of interest using both a univariate differentiation index and multivoxel pattern similarity analysis. Both methods provided highly convergent results which revealed evidence of age-related reductions in neural dedifferentiation in scene-selective but not face-selective cortical regions. Additionally, neural differentiation in the parahippocampal place area demonstrated a positive, age-invariant relationship with subsequent source memory performance (recall of the image category paired with each recognized test word). These findings extend prior findings suggesting that age-related neural dedifferentiation is not a ubiquitous phenomenon, and that the specificity of neural responses to scenes is predictive subsequent memory performance independently of age.Significance StatementIncreasing age is associated with reduced neural specificity in cortical regions that are selectively responsive to a given perceptual stimulus category (age-related neural dedifferentiation), a phenomenon which has been proposed to contribute to cognitive aging. Recent findings reveal that age-related neural dedifferentiation is not present for all types of visual stimulus categories, and the factors which determine when the phenomenon arises remain unclear. Here, we demonstrate that scene- but not face-selective cortical regions exhibit age-related neural dedifferentiation during an attentionally-demanding task. Additionally, we report that higher neural selectivity in the scene-selective ‘parahippocampal place area’ is associated with better memory performance after controlling for variance associated with age group, adding to evidence that neural differentiation impacts cognition across the adult lifespan.

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.

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