scholarly journals Circuit mechanisms underlying chronic epilepsy in a mouse model of focal cortical malformation

2020 ◽  
Author(s):  
Weiguo Yang ◽  
Anthony Williams ◽  
Qian-Quan Sun
Keyword(s):  
Mouse Model ◽  
Closed Loop ◽  
Pyramidal Neurons ◽  
Cortical Region ◽  
Cortical Malformation ◽  
Optogenetic Stimulation ◽  
Layer 2 ◽  
Spike Wave Discharges ◽  
Spike Wave

HighlightsEctopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons is a key component of the hyperexcitable circuitryDisrupted E/I balance was located far away from cortical malformationsDendritic inhibition from somatostatin interneurons play a key role in epileptogenesisClosed-loop optogenetic stimulation to activate remainder somatostatin interneurons irreversibly stops the spontaneous spike-wave discharges in vivo.In BriefYang et al. report abnormal synaptic reorganization in an epileptogenesis zone in a mouse model of cortical malformation. The authors further demonstrate that spontaneous spike-wave discharges can be curbed by selectively activating somatostatin interneurons using close-loop fiber optogenetic stimulation to a small cortical region away from the microgyrus.SummaryHow aberrant neural circuits contribute to chronic epilepsy remains unclear. Using a mouse model of focal cortical malformation with spontaneous seizures, we dissected the circuit mechanisms underlying epileptogenesis. Spontaneous and optogenetically induced hyperexcitable bursts in vivo were present in a cortical region distal to (> 1mm) freeze-lesion induced microgyrus, instead of a region near it. ChR2-assisted circuit mapping revealed ectopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons as a key component of the hyperexcitable circuitry. This disrupted balance between excitation and inhibition was prominent in the cortical region distal to the microgyrus. Consistently, the synapses of both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were maladaptive in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate highly site- and cell-type specific synaptic reorganization underlying chronic cortical epilepsy and provide insights into potential treatment strategies for this devastating neurological disorder.

scholarly journals Regulatory Mechanism for Absence Seizures in Bidirectional Interactive Thalamocortical Model via Different Targeted Therapy Schemes

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Hudong Zhang ◽  
Xiaolong Tan ◽  
Yufeng Pan ◽  
Yuan Chai
Keyword(s):  
Targeted Therapy ◽  
Regulatory Mechanism ◽  
Cortical Region ◽  
Neural Pathways ◽  
Absence Seizures ◽  
Theoretical Simulation ◽  
Biphasic Pulse ◽  
Bidirectional Communication ◽  
Spike Wave Discharges ◽  
Spike Wave

Recent clinical practice has found that the spike-wave discharge (SWD) scopes of absence seizures change from small cortical region to large thalamocortical networks, which has also been proved by theoretical simulation. The best biophysics explanation is that there are interactions between coupled cortico-thalamic and thalamocortical circuits. To agree with experiment results and describe the phenomena better, we constructed a coupled thalamocortical model with bidirectional channel (CTMBC) to account for the causes of absence seizures which are connected by the principle of two-way communication of neural pathways. By adjusting the coupling strength of bidirectional pathways, the spike-wave discharges are reproduced. Regulatory mechanism for absence seizures is further applied to CTMBC via four different targeted therapy schemes, such as deep brain stimulation (DBS), charge-balanced biphasic pulse (CBBP), coordinated reset stimulation (CRS) 1 : 0, and (CRS) 3 : 2. The new CTMBC model shows that neurodiversity in bidirectional interactive channel could supply theory reference for the bidirectional communication mode of thalamocortical networks and the hypothesis validation of pathogenesis.

scholarly journals Asymmetric Temporal Integration of Layer 4 and Layer 2/3 Inputs in Visual Cortex

2011 ◽  
Vol 105 (1) ◽  
pp. 347-355 ◽  
Author(s):  
Giao B. Hang ◽  
Yang Dan
Keyword(s):  
Visual Cortex ◽  
Visual Processing ◽  
Pyramidal Neurons ◽  
Temporal Integration ◽  
Cortical Inhibition ◽  
Multiple Sources ◽  
Layer 2 ◽  
Layer 4 ◽  
The Difference

Neocortical neurons in vivo receive concurrent synaptic inputs from multiple sources, including feedforward, horizontal, and feedback pathways. Layer 2/3 of the visual cortex receives feedforward input from layer 4 and horizontal input from layer 2/3. Firing of the pyramidal neurons, which carries the output to higher cortical areas, depends critically on the interaction of these pathways. Here we examined synaptic integration of inputs from layer 4 and layer 2/3 in rat visual cortical slices. We found that the integration is sublinear and temporally asymmetric, with larger responses if layer 2/3 input preceded layer 4 input. The sublinearity depended on inhibition, and the asymmetry was largely attributable to the difference between the two inhibitory inputs. Interestingly, the asymmetric integration was specific to pyramidal neurons, and it strongly affected their spiking output. Thus via cortical inhibition, the temporal order of activation of layer 2/3 and layer 4 pathways can exert powerful control of cortical output during visual processing.

scholarly journals The NMDA-to-AMPA Ratio at Synapses Onto Layer 2/3 Pyramidal Neurons Is Conserved Across Prefrontal and Visual Cortices

2003 ◽  
Vol 90 (2) ◽  
pp. 771-779 ◽  
Author(s):  
Chaelon I. O. Myme ◽  
Ken Sugino ◽  
Gina G. Turrigiano ◽  
Sacha B. Nelson
Keyword(s):  
Ampa Receptor ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Cell Voltage ◽  
Decay Kinetics ◽  
Excitatory Transmission ◽  
Layer 2 ◽  
Medial Pfc

To better understand regulation of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complements across the cortex, and to investigate NMDA receptor (NMDAR)-based models of persistent activity, we compared NMDA/AMPA ratios in prefrontal (PFC) and visual cortex (VC) in rat. Whole cell voltage-clamp responses were recorded in brain slices from layer 2/3 pyramidal cells of the medial PFC and VC of rats aged p16–p21. Mixed miniature excitatory postsynaptic currents (mEPSCs) having AMPA receptor (AMPAR)- and NMDAR-mediated components were isolated in nominally 0 Mg2+ ACSF. Averaged mEPSCs were well-fit by double exponentials. No significant differences in the NMDA/AMPA ratio (PFC: 27 ± 1%; VC: 28 ± 3%), peak mEPSC amplitude (PFC: 19.1 ± 1 pA; VC: 17.5 ± 0.7 pA), NMDAR decay kinetics (PFC: 69 ± 8 ms; VC: 67 ± 6 ms), or degree of correlation between NMDAR- and AMPAR-mediated mEPSC components were found between the areas (PFC: n = 27; VC: n = 28). Recordings from older rats (p26–29) also showed no differences. EPSCs were evoked extracellularly in 2 mM Mg2+ at depolarized potentials; although the average NMDA/AMPA ratio was larger than that observed for mEPSCs, the ratio was similar in the two regions. In nominally 0 Mg2+ and in the presence of CNQX, spontaneous activation of NMDAR increased recording noise and produced a small tonic depolarization which was similar in both areas. We conclude that this basic property of excitatory transmission is conserved across PFC and VC synapses and is therefore unlikely to contribute to differences in firing patterns observed in vivo in the two regions.

Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo

10.1038/4569 ◽  
1999 ◽  
Vol 2 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Karel Svoboda ◽  
Fritjof Helmchen ◽  
Winfried Denk ◽  
David W. Tank
Keyword(s):  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Layer 2

scholarly journals Cerebellar Contribution to Absence Epilepsy

2020 ◽  
Author(s):  
Leonid S. Godlevsky ◽  
Oleh R. Pinyazhko ◽  
Olesya B. Poshyvak
Keyword(s):  
Epileptic Activity ◽  
Absence Epilepsy ◽  
Absence Seizure ◽  
Imaging Data ◽  
Optogenetic Stimulation ◽  
Different Types ◽  
Spike Wave Discharges ◽  
Deep Brain ◽  
Spike Wave

ABSTRACTThe new aggregate data analyses revealed the earlier missing role played by the cerebellum long-term electrical stimulation in the absence epilepsy. Neurophysiologic data gained by authors favor that cerebellar serial deep brain stimulation (DBS) (100 Hz) causes the transformation of penicillin-induced cortical focal discharges into prolonged 3,5-3,75 sec oscillations resembling spike-wave discharges (SWD) in cats. Such SWDs were not organized in the form of bursts and persisted continuously after stimulation. Therefore the appearance of prolonged periods of SWD is regarded as a tonic cerebellar influence upon pacemaker of SWD and might be caused by the long-lasting DBS-induced increase of GABA-ergic extrasynaptic inhibition in forebrain networks. At the same time, cerebellar DBS high-frequency (100 Hz) suppressed bursts of SWD observed during the phase of stimulation. Different types of cerebellar DBS upon epileptic activity emphasized the absence seizure facilitation discussed with the reviewed data on optogenetic stimulation, neuronal activity of cerebellar structures, and functional magnetic resonance imaging data.

Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia

2021 ◽  
Author(s):  
Diego E Pafundo ◽  
Carlos A Pretell Annan ◽  
Nicolas M Fulginiti ◽  
Juan E Belforte
Keyword(s):  
Prefrontal Cortex ◽  
Mouse Model ◽  
Pyramidal Neurons ◽  
Gamma Oscillations ◽  
Dependent Manner ◽  
Early Postnatal Development ◽  
Synaptic Inputs ◽  
Selective Ablation ◽  
Activity Dependent

Abstract Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.

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.

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