scholarly journals Endocannabinoid-Mediated Control of Neural Circuit Excitability and Epileptic Seizures

2022 ◽  
Vol 15 ◽  
Author(s):  
Yuki Sugaya ◽  
Masanobu Kano
Keyword(s):  
Neural Circuit ◽  
Glutamate Release ◽  
Epileptic Seizures ◽  
Gaba Release ◽  
Signaling Molecules ◽  
Dravet Syndrome ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Spontaneous Seizures ◽  
Health And Disease

Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.

Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

2020 ◽  
Vol 13 (663) ◽  
pp. eabd8379
Author(s):  
Heba Ali ◽  
Lena Marth ◽  
Dilja Krueger-Burg
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inhibitory Synapses ◽  
Molecular Architecture ◽  
Cellular Functions ◽  
Altered Expression ◽  
Health And Disease ◽  
Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

scholarly journals Dynamic structural neuroplasticity during and after epileptogenesis in a pilocarpine rat model of epilepsy

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Soomaayeh Heysieattalab ◽  
Leila Sadeghi
Keyword(s):  
Rat Model ◽  
Chronic Phase ◽  
Structural Plasticity ◽  
Epileptic Seizures ◽  
Experimental Models ◽  
Spontaneous Seizures ◽  
Maladaptive Plasticity ◽  
Male Wistar Rats ◽  
Spontaneous Recurrent Seizures ◽  
Latent Phase

Abstract Background The role of neuroplasticity in epilepsy has been widely studied in experimental models and human brain samples. However, the results are contradictory and it remains unclear if neuroplasticity is more related to the cause or the consequence of epileptic seizures. Clarifying this issue can provide insights into epilepsy therapies that target the disease mechanism and etiology rather than symptoms. Therefore, this study was aimed to investigate the dynamic changes of structural plasticity in a pilocarpine rat model of epilepsy. Methods A single acute dose of pilocarpine (380 mg/kg, i.p.) was injected into adult male Wistar rats to induce status epilepticus (SE). Animal behavior was monitored for 2 h. Immunohistochemical staining was performed to evaluate neurogenesis in the CA3 and dentate gyrus (DG) regions of hippocampus using biomarkers Ki67 and doublecortin (DCX). The Golgi-Cox method was performed to analyze dendritic length and complexity. All experiments were performed in control rats (baseline), at 24 h after SE, on day 20 after SE (latent phase), after the first and 10th spontaneous recurrent seizures (SRS; chronic phase), and in non-epileptic rats (which did not manifest SRS 36 days after pilocarpine injection). Results SE significantly increased the number of Ki67 and DCX-positive cells, suggesting neurogenesis during the latent phase. The dendritic complexity monitoring showed that plasticity was altered differently during epilepsy and epileptogenesis, suggesting that the two processes are completely separate at molecular and physiological levels. The numbers of spines and mushroom-type spines were increased in the latent phase. However, the dendritogenesis and spine numbers did not increase in rats that were unable to manifest spontaneous seizures after SE. Conclusion All parameters of structural plasticity that increase during epileptogenesis, are reduced by spontaneous seizure occurrence, which suggests that the development of epilepsy involves maladaptive plastic changes. Therefore, the maladaptive plasticity biomarkers can be used to predict epilepsy before development of SRS in the cases of serious brain injury.

scholarly journals Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity

2018 ◽  
Vol 25 (5) ◽  
pp. 455-474 ◽  
Author(s):  
Colm Cunningham ◽  
Aisling Dunne ◽  
Ana Belen Lopez-Rodriguez
Keyword(s):  
Neural Circuit ◽  
Phenotypic Diversity ◽  
Significant Heterogeneity ◽  
Therapeutic Implications ◽  
Numerous Cell ◽  
Health And Disease ◽  
The Subject ◽  
The Brain ◽  
Substantial Heterogeneity ◽  
Homogenous Population

Astrocytes are the most numerous cell type in the brain and perform several essential functions in supporting neuronal metabolism and actively participating in neural circuit and behavioral function. They also have essential roles as innate immune cells in responding to local neuropathology, and the manner in which they respond to brain injury and degeneration is the subject of increasing attention in neuroscience. Although activated astrocytes have long been thought of as a relatively homogenous population, which alter their phenotype in a relatively stereotyped way upon central nervous system injury, the last decade has revealed substantial heterogeneity in the basal state and significant heterogeneity of phenotype during reactive astrocytosis. Thus, phenotypic diversity occurs at two distinct levels: that determined by regionality and development and that determined by temporally dynamic changes to the environment of astrocytes during pathology. These inflammatory and pathological states shape the phenotype of these cells, with different consequences for destruction or recovery of the local tissue, and thus elucidating these phenotypic changes has significant therapeutic implications. In this review, we will focus on the phenotypic heterogeneity of astrocytes in health and disease and their propensity to change that phenotype upon subsequent stimuli.

scholarly journals GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells

2018 ◽  
Vol 115 (51) ◽  
pp. E12083-E12090 ◽  
Author(s):  
Adam Bleckert ◽  
Chi Zhang ◽  
Maxwell H. Turner ◽  
David Koren ◽  
David M. Berson ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Selective Reduction ◽  
Amacrine Cells ◽  
Gaba Release ◽  
Direction Selectivity ◽  
Inhibitory Synapses ◽  
Retinal Ganglion ◽  
Gabaergic Transmission ◽  
Starburst Amacrine Cells ◽  
Receptor Clusters

Synaptic inhibition controls a neuron’s output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on–off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC’s soma and dendrites could facilitate homeostatic control of the ooDSGC’s output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.

Electrophysiological evidence from glutamate microapplications for local excitatory circuits in the CA1 area of rat hippocampal slices

1988 ◽  
Vol 59 (1) ◽  
pp. 110-123 ◽  
Author(s):  
E. P. Christian ◽  
F. E. Dudek
Keyword(s):  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Recording Site ◽  
Postsynaptic Potentials ◽  
Inhibitory Postsynaptic Potentials ◽  
Ca1 Area ◽  
Transverse Slice

1. Evidence for local excitatory synaptic connections in CA1 of the rat hippocampus was obtained by recording excitatory postsynaptic potentials (EPSPs) intracellularly from pyramidal cells during local microapplications of glutamate. 2. Experiments were performed in hippocampal slices cut parallel to (transverse slice) or perpendicular to (longitudinal slice) alvear fibers. In normal solutions, glutamate microdrops (10–20 mM, 10–20 micron diam) applied in CA1 within 400 micron of recorded cells sometimes increased the frequency of inhibitory postsynaptic potentials for 5–10 s in both transverse and longitudinal slices. Increases in EPSP frequency were also occasionally observed, but only in transverse slices. Tetrodotoxin (1 microgram/ml) blocked glutamate-induced increases in PSP frequency, thus indicating that they were not caused by subthreshold effects on presynaptic terminals. Increases in PSP frequency were interpreted to result from glutamate activation of hippocampal neurons with inhibitory and excitatory connections to recorded neurons. 3. In both slice orientations, local excitatory circuits were studied in more isolated conditions by surgically separating CA1 from CA3 (transverse slices) and by blocking GABAergic inhibitory synapses with picrotoxin (5–10 microM). Microdrops were systematically applied at 200 and 400 micron on each side of the recording site. Significant glutamate-induced increases in EPSP frequency were observed in neurons from both slice orientations to microdrops in at least one of the locations. This provided evidence that excitatory synapses are present in both transverse and longitudinal slices. 4. Substantial increases in EPSP frequency only occurred in neurons from longitudinal slices when glutamate was microapplied 200 micron or less from the recording site. In transverse slices, however, large increases in EPSP frequency were observed to glutamate microapplications at 200 or 400 micron. These data suggest that CA1 local excitatory connections project for longer distances in the transverse than in the longitudinal plane of section. 5. Increases in EPSP frequency, averaged across cells, did not differ significantly in the four microapplication sites in either transverse or longitudinal slices. Thus local excitation in CA1 does not appear to be asymmetrically arranged in the way suggested for CA3. 6. The densities of local excitatory circuits in CA1 versus CA3 were studied by quantitatively comparing glutamate-induced increases in EPSP frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Vaishali Satpute Janve ◽  
Lyndsey L. Anderson ◽  
Dilara Bahceci ◽  
Nicole A. Hawkins ◽  
Jennifer A. Kearney ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Target ◽  
Genetic Modifier ◽  
Anticonvulsant Drug ◽  
Dravet Syndrome ◽  
Seizure Threshold ◽  
Drug Resistant ◽  
Spontaneous Seizures ◽  
Temperature Thresholds ◽  
Seizure Models

Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/− mouse model of DS. We found that cortical Trpv1 mRNA expression was increased in seizure susceptible F1.Scn1a+/− mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/− mice isogenic on 129S6/SvEvTac background, suggesting Trpv1 could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/− mice. Surprisingly, Trpv1 deletion had both pro- and anti-seizure effects. Trpv1 deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−; Trpv1+/− at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, Trpv1 deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/− model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.

scholarly journals Anesthetic Management of Patient With Dravet Syndrome: A Case Report

2019 ◽  
Vol 66 (3) ◽  
pp. 156-158 ◽  
Author(s):  
Naohiro Ohshita ◽  
Kaname Tsuji ◽  
Hiroaki Yoshida ◽  
Hiroki Shibata ◽  
Yoshiko Matsuda ◽  
...  
Keyword(s):  
Body Temperature ◽  
Adverse Events ◽  
Anesthetic Management ◽  
Epileptic Seizures ◽  
Severe Form ◽  
Dravet Syndrome ◽  
Temperature Management ◽  
Intravenous Sedation ◽  
Medical Procedures ◽  
Slight Fever

Dravet syndrome (DS) is a rare and severe form of epilepsy that begins in infancy. This is particularly burdensome because repeated epileptic seizures lead to cognitive decline. We describe the case of a 12-year-old girl who was diagnosed with DS and was scheduled to have gingival reduction around her mandibular molars. Despite the patient being intellectually disabled, she was able to cooperate somewhat during medical procedures, including intravenous cannulation. Under the assumption that the major problem with anesthesia for DS would be the regulation of body temperature–induced seizures, we used body temperature management equipment to maintain the patient's body temperature during the procedure. We opted for intravenous sedation and administered a total dose of 4.5 mg midazolam throughout the procedure. Anesthesia was completed within 1 hour and 20 minutes without any adverse events. To the best of our knowledge, no previous studies have documented the anesthetic management of DS. In this case, no adverse events occurred perioperatively. However, the patient's temperature rose to that which indicated a slight fever despite the use of a standard cooling technique.

Synaptic Regulation of Proopiomelanocortin Neurons Can Occur Distal to the Arcuate Nucleus

2007 ◽  
Vol 97 (5) ◽  
pp. 3298-3304 ◽  
Author(s):  
Shane T. Hentges
Keyword(s):  
Cell Body ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Critical Role ◽  
Brain Slices ◽  
Gaba Release ◽  
Afferent Input ◽  
Inhibitory Synapses ◽  
Body Region ◽  
Neuron Activity

Energy homeostasis is controlled to a large extent by various signals that are integrated in the hypothalamus. It is generally considered that neurons in each of the hypothalamic nuclei are regulated by afferent projections that terminate within the cell body region of the nucleus. However, here it is shown that hypothalamic proopiomelanocortin (POMC) neurons receive synaptic inputs onto distal dendrites that reside outside of the cell body region in the arcuate nucleus. Previous studies using whole cell recordings from identified neurons in brain slices have shown that cannabinoids reduce GABA release from inhibitory synapses onto the POMC cells. Here it was found that endocannabinoids inhibited GABAergic inhibitory postsynaptic currents in POMC neurons only in intact sagittal brain slices, but not coronal, horizontal, or sagittal slices that were truncated rostrally at the level of the optic chiasm. Thus endocannabinoids inhibited presynaptic GABA release only at an anatomically distinct subset of POMC–neuron dendrites that extends rostrally beyond the arcuate nucleus into preoptic hypothalamic regions. There are two key results. First, the activity of POMC neurons can be regulated by afferent input at sites much farther from the soma than previously recognized. Second, endocannabinoids can act to inhibit inputs only at selective dendrites. POMC neurons play a critical role in the maintenance of body weight. Therefore these data suggest that energy balance may be regulated, in part, by modulation of POMC neuron activity at sites outside of the arcuate nucleus.

scholarly journals Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

2020 ◽  
Vol 117 (12) ◽  
pp. 6708-6716 ◽  
Author(s):  
Maryann P. Platt ◽  
Kevin A. Bolding ◽  
Charlotte R. Wayne ◽  
Sarah Chaudhry ◽  
Tyler Cutforth ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Neural Circuit ◽  
Psychiatric Symptoms ◽  
Neuropsychiatric Symptoms ◽  
Autoimmune Encephalitis ◽  
Abrupt Onset ◽  
Synaptic Proteins ◽  
Excitatory Synapses ◽  
Odor Processing ◽  
Th17 Lymphocytes

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group AStreptococcus(GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood–brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB). Whether these pathologies induce functional olfactory deficits, and the mechanistic role of Th17 lymphocytes, is unknown. Here, we demonstrate that, whereas loss of excitatory synapses in the OB is transient after multiple GAS infections, functional deficits in odor processing persist. Moreover, mice lacking Th17 lymphocytes have reduced BBB leakage, microglial activation, and antibody infiltration into the CNS, and have their olfactory function partially restored. Th17 lymphocytes are therefore critical for selective CNS entry of autoantibodies, microglial activation, and neural circuit impairment during postinfectious BGE.

scholarly journals Synapse-Specific Homeostatic Mechanisms in the Hippocampus

2009 ◽  
Vol 101 (2) ◽  
pp. 503-506 ◽  
Author(s):  
Katherine E. Deeg
Keyword(s):  
Neural Circuits ◽  
Epileptic Seizures ◽  
Homeostatic Plasticity ◽  
Excitatory Synapses ◽  
Network Stability ◽  
Homeostatic Synaptic Plasticity ◽  
New Type ◽  
Hippocampal Network ◽  
Synaptic Gain ◽  
Different Populations

Homeostatic synaptic plasticity allows neural circuits to function stably despite fluctuations to their inputs. Previous work has shown that excitatory synaptic strength increases globally when neuronal inputs are chronically silenced. A recent paper by Kim and Tsien describes a new type of synapse-specific homeostatic plasticity in which input silencing causes simultaneous strengthening and weakening of different populations of excitatory synapses within a hippocampal network. These seemingly antagonistic homeostatic adaptations maintain synaptic gain and preserve overall network stability by limiting harmful reverberatory bursting, which may underlie epileptic seizures.

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