scholarly journals Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy

2020 ◽  
Vol 48 (4) ◽  
pp. E18
Author(s):  
Stephen C. Harward ◽  
Derek G. Southwell
Keyword(s):  
Surgical Therapy ◽  
Neural Circuits ◽  
Refractory Epilepsy ◽  
Brain Parenchyma ◽  
Inhibitory Synapses ◽  
Human Epilepsy ◽  
Physiological Processes ◽  
Behavioral Abnormalities ◽  
Cortical Interneurons ◽  
Network Synchrony

Excitatory-inhibitory imbalance is central to epilepsy pathophysiology. Current surgical therapies for epilepsy, such as brain resection, laser ablation, and neurostimulation, target epileptic networks on macroscopic scales, without directly correcting the circuit-level aberrations responsible for seizures. The transplantation of inhibitory cortical interneurons represents a novel neurobiological method for modifying recipient neural circuits in a physiologically corrective manner. Transplanted immature interneurons have been found to disperse in the recipient brain parenchyma, where they develop elaborate structural morphologies, express histochemical markers of mature interneurons, and form functional inhibitory synapses onto recipient neurons. Transplanted interneurons also augment synaptic inhibition and alter recipient neural network synchrony, two physiological processes disrupted in various epilepsies. In rodent models of epilepsy, interneuron transplantation corrects recipient seizure phenotypes and associated behavioral abnormalities. As such, interneuron transplantation may represent a novel neurobiological approach to the surgical treatment of human epilepsy. Here, the authors describe the preclinical basis for applying interneuron transplantation to human epilepsy, discuss its potential clinical applications, and consider the translational hurdles to its development as a surgical therapy.

scholarly journals Properties of precise firing synchrony between synaptically coupled cortical interneurons depend on their mode of coupling

2015 ◽  
Vol 114 (1) ◽  
pp. 624-637 ◽  
Author(s):  
Hang Hu ◽  
Ariel Agmon
Keyword(s):  
Firing Rate ◽  
Electrical Coupling ◽  
Gamma Oscillations ◽  
Inhibitory Synapses ◽  
Data Set ◽  
Temporal Precision ◽  
Gamma Frequency ◽  
Rate Dependent ◽  
Cortical Interneurons

Precise spike synchrony has been widely reported in the central nervous system, but its functional role in encoding, processing, and transmitting information is yet unresolved. Of particular interest is firing synchrony between inhibitory cortical interneurons, thought to drive various cortical rhythms such as gamma oscillations, the hallmark of cognitive states. Precise synchrony can arise between two interneurons connected electrically, through gap junctions, chemically, through fast inhibitory synapses, or dually, through both types of connections, but the properties of synchrony generated by these different modes of connectivity have never been compared in the same data set. In the present study we recorded in vitro from 152 homotypic pairs of two major subtypes of mouse neocortical interneurons: parvalbumin-containing, fast-spiking (FS) interneurons and somatostatin-containing (SOM) interneurons. We tested firing synchrony when the two neurons were driven to fire by long, depolarizing current steps and used a novel synchrony index to quantify the strength of synchrony, its temporal precision, and its dependence on firing rate. We found that SOM-SOM synchrony, driven solely by electrical coupling, was less precise than FS-FS synchrony, driven by inhibitory or dual coupling. Unlike SOM-SOM synchrony, FS-FS synchrony was strongly firing rate dependent and was not evident at the prototypical 40-Hz gamma frequency. Computer simulations reproduced these differences in synchrony without assuming any differences in intrinsic properties, suggesting that the mode of coupling is more important than the interneuron subtype. Our results provide novel insights into the mechanisms and properties of interneuron synchrony and point out important caveats in current models of cortical oscillations.

scholarly journals Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

2020 ◽  
Author(s):  
Jelena Scekic-Zahirovic ◽  
Inmaculada Sanjuan-Ruiz ◽  
Vanessa Kan ◽  
Salim Megat ◽  
Pierre De Rossi ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Rna Binding ◽  
Gene Mutations ◽  
Neuronal Loss ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Behavioral Alterations ◽  
Behavioral Abnormalities ◽  
Cytoplasmic Accumulation

AbstractGene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

Surgical therapy for medically intractable epilepsy

1987 ◽  
Vol 66 (4) ◽  
pp. 489-499 ◽  
Author(s):  
George A. Ojemann
Keyword(s):  
Temporal Lobe ◽  
Surgical Therapy ◽  
Imaging Techniques ◽  
Intractable Epilepsy ◽  
Content Type ◽  
Human Epilepsy ◽  
Depth Electrodes ◽  
Positron Emission ◽  
Intraoperative Management ◽  
Fine Print

✓ There has been a recent renewal of interest in surgical therapy for medically intractable epilepsies. Cortical resection and callosotomy are the most widely accepted modes of surgical management. The indications for each of these approaches are reviewed. Although there has been much interest in imaging techniques, including positron emission tomography, to identify epileptogenic zones, identification still depends primarily on the electroencephalogram (EEG). There are several approaches to the evaluation and intraoperative management of patients undergoing cortical resection for temporal lobe epileptogenic zones. These range from selection based on scalp interictal EEG criteria, with resections guided by electrocorticography and functional mapping, to selection based on the location of ictal onset as recorded by chronically implanted depth electrodes, with an anatomically standard resection of the temporal lobe or resection limited to amygdalohippocampectomy. No one approach provides the optimum balance of benefits to risks and costs for all patients. The relative value of the different approaches for various populations of patients with medically intractable partial complex seizures is reviewed. Techniques for minimizing the morbidity of these operations, especially in regard to language and memory, are also discussed, as are the contributions to an understanding of the neurobiology of human epilepsy and human higher functions derived from the surgical therapy of epilepsy.

scholarly journals Synaptic Hyaluronan Synthesis and CD44-Mediated Signaling Coordinate Neural Circuit Development

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2574
Author(s):  
Emily S. Wilson ◽  
Karen Litwa
Keyword(s):  
Mouse Brain ◽  
Synapse Formation ◽  
Neural Circuits ◽  
Neural Circuit ◽  
System Development ◽  
Synaptic Cleft ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Perineuronal Nets ◽  
Potential Formation

The hyaluronan-based extracellular matrix is expressed throughout nervous system development and is well-known for the formation of perineuronal nets around inhibitory interneurons. Since perineuronal nets form postnatally, the role of hyaluronan in the initial formation of neural circuits remains unclear. Neural circuits emerge from the coordinated electrochemical signaling of excitatory and inhibitory synapses. Hyaluronan localizes to the synaptic cleft of developing excitatory synapses in both human cortical spheroids and the neonatal mouse brain and is diminished in the adult mouse brain. Given this developmental-specific synaptic localization, we sought to determine the mechanisms that regulate hyaluronan synthesis and signaling during synapse formation. We demonstrate that hyaluronan synthase-2, HAS2, is sufficient to increase hyaluronan levels in developing neural circuits of human cortical spheroids. This increased hyaluronan production reduces excitatory synaptogenesis, promotes inhibitory synaptogenesis, and suppresses action potential formation. The hyaluronan receptor, CD44, promotes hyaluronan retention and suppresses excitatory synaptogenesis through regulation of RhoGTPase signaling. Our results reveal mechanisms of hyaluronan synthesis, retention, and signaling in developing neural circuits, shedding light on how disease-associated hyaluronan alterations can contribute to synaptic defects.

scholarly journals Emergence of synaptic organization and computation in dendrites

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Jan H. Kirchner ◽  
Julijana Gjorgjieva
Keyword(s):  
Neural Circuits ◽  
Spatial Scales ◽  
Theoretical Research ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Synaptic Organization ◽  
Synaptic Inputs ◽  
Multiple Spatial Scales ◽  
Neural Computations ◽  
The Brain

Abstract Single neurons in the brain exhibit astounding computational capabilities, which gradually emerge throughout development and enable them to become integrated into complex neural circuits. These capabilities derive in part from the precise arrangement of synaptic inputs on the neurons’ dendrites. While the full computational benefits of this arrangement are still unknown, a picture emerges in which synapses organize according to their functional properties across multiple spatial scales. In particular, on the local scale (tens of microns), excitatory synaptic inputs tend to form clusters according to their functional similarity, whereas on the scale of individual dendrites or the entire tree, synaptic inputs exhibit dendritic maps where excitatory synapse function varies smoothly with location on the tree. The development of this organization is supported by inhibitory synapses, which are carefully interleaved with excitatory synapses and can flexibly modulate activity and plasticity of excitatory synapses. Here, we summarize recent experimental and theoretical research on the developmental emergence of this synaptic organization and its impact on neural computations.

scholarly journals Non-Transgenic Functional Rescue of Neuropeptides

2021 ◽  
Author(s):  
Elizabeth DiLoreto ◽  
Douglas Reilly ◽  
Jagan Sriniva
Keyword(s):  
High Throughput Screening ◽  
Neural Circuits ◽  
Screening Strategy ◽  
Loss Of Function ◽  
Active Peptides ◽  
Physiological Processes ◽  
Internal States ◽  
Multiple Copies ◽  
Escherichia Coli Bacteria ◽  
Peptide Uptake

Abstract Animals constantly respond to changes in their environment and internal states via neuromodulation. Neuropeptide genes modulate neural circuits by encoding either multiple copies of the same neuropeptide or different neuropeptides. This architectural complexity makes it difficult to determine the function of discrete and active neuropeptides. Here, we present a novel genetic tool that facilitates functional analysis of individual peptides. We engineered Escherichia coli bacteria to express active peptides and fed loss-of-function Caenorhabditis elegans to rescue gene activity. Using this approach, we rescued the activity of different neuropeptide genes with varying lengths and functions: trh-1, ins-6, and pdf-1. While some peptides are functionally redundant, others exhibited unique and previously uncharacterized functions. The mechanism of peptide uptake is reminiscent of RNA interference, suggesting convergent mechanisms of gene regulation in organisms. Our rescue-by-feeding paradigm provides a high-throughput screening strategy to elucidate the functional landscape of neuropeptide genes regulating different behavioral and physiological processes.

scholarly journals Synaptic control of spinal GRPR+neurons by local and long-range inhibitory inputs

2019 ◽  
Vol 116 (52) ◽  
pp. 27011-27017 ◽  
Author(s):  
Ming-Zhe Liu ◽  
Xiao-Jun Chen ◽  
Tong-Yu Liang ◽  
Qing Li ◽  
Meng Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Long Range ◽  
Neural Circuits ◽  
Rostral Ventromedial Medulla ◽  
Inhibitory Synapses ◽  
Peptide Receptor ◽  
Gastrin Releasing Peptide ◽  
Ventromedial Medulla ◽  
Synaptic Control ◽  
Oxide Synthase

Spinal gastrin-releasing peptide receptor-expressing (GRPR+) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR+neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR+neurons. We found that spinal galanin+GABAergic neurons form inhibitory synapses with GRPR+neurons in the spinal cord and play an important role in gating the GRPR+neuron-dependent itch signaling pathway. Spinal GRPR+neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR+neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs could play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR+neurons.

scholarly journals Non-Transgenic Functional Rescue of Neuropeptides

2021 ◽  
Author(s):  
Elizabth M DiLoreto ◽  
Douglas K Reilly ◽  
Jagan Srinivasan
Keyword(s):  
High Throughput Screening ◽  
Neural Circuits ◽  
Screening Strategy ◽  
Loss Of Function ◽  
Active Peptides ◽  
Physiological Processes ◽  
Internal States ◽  
Multiple Copies ◽  
Escherichia Coli Bacteria ◽  
Peptide Uptake

Animals constantly respond to changes in their environment and internal states via neuromodulation. Neuropeptide genes modulate neural circuits by encoding either multiple copies of the same neuropeptide or different neuropeptides. This architectural complexity makes it difficult to determine the function of discrete and active neuropeptides. Here, we present a novel genetic tool that facilitates functional analysis of individual peptides. We engineered Escherichia coli bacteria to express active peptides and fed loss-of-function Caenorhabditis elegans to rescue gene activity. Using this approach, we rescued the activity of different neuropeptide genes with varying lengths and functions: trh-1, ins-6, and pdf-1. While some peptides are functionally redundant, others exhibited unique and previously uncharacterized functions. The mechanism of peptide uptake is reminiscent of RNA interference, suggesting convergent mechanisms of gene regulation in organisms. Our rescue-by-feeding paradigm provides a high-throughput screening strategy to elucidate the functional landscape of neuropeptide genes regulating different behavioral and physiological processes.

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