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Modeling "psychosis" in vitro by inducing disordered neuronal network activity in cortical brain slices.

ABSTRACT: INTRODUCTION: Dysregulation of neuronal networks has been suggested to underlie the cognitive and perceptual abnormalities observed schizophrenia. DISCUSSIONS: An in vitro model of psychosis is proposed based on the two different approaches to cause aberrant network activity in layer V pyramidal cells of prefrontal brain slices: (1) psychedelic hallucinogens such as lysergic acid diethylamide and (2) minimal GABA(A) receptor antagonism, modeling the GABA interneuron deficit in schizophrenia. A test of this model would be to determine if drugs that normalize aberrant networks in brain slices have efficacy in the treatment of schizophrenia. Selective agonists of glutamate mGlu2/3 metabotropic receptors, which are highly effective in suppressing aberrant network activity in slices, are the most advanced toward reaching that clinical endpoint. In accord with the model, a recent phase II clinical trial shows that an mGlu2/3 receptor agonist is equivalent in efficacy to a standard antipsychotic drug for both negative and positive symptoms in schizophrenic patients, but without the usual side effects. D1/5 dopamine receptor agonists are also effective in normalizing aberrant network activity induced by both hallucinogens and minimal GABA(A) antagonism; clinical efficacy remains to be determined. A general model of network regulation is presented, involving astrocytes, GABA interneurons, and glutamatergic pyramidal cells, revealing a wide range of potential sites hitherto not considered as therapeutic targets.

SUBMITTER: Aghajanian GK

PROVIDER: S-EPMC2755104 | biostudies-other | 2009 Nov

REPOSITORIES: biostudies-other

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Characterization of cortical neuronal and glial alterations during culture of organotypic whole brain slices from neonatal and mature mice.

Project description:BackgroundOrganotypic brain slice culturing techniques are extensively used in a wide range of experimental procedures and are particularly useful in providing mechanistic insights into neurological disorders or injury. The cellular and morphological alterations associated with hippocampal brain slice cultures has been well established, however, the neuronal response of mouse cortical neurons to culture is not well documented.MethodsIn the current study, we compared the cell viability, as well as phenotypic and protein expression changes in cortical neurons, in whole brain slice cultures from mouse neonates (P4-6), adolescent animals (P25-28) and mature adults (P50+). Cultures were prepared using the membrane interface method.ResultsPropidium iodide labeling of nuclei (due to compromised cell membrane) and AlamarBlue™ (cell respiration) analysis demonstrated that neonatal tissue was significantly less vulnerable to long-term culture in comparison to the more mature brain tissues. Cultures from P6 animals showed a significant increase in the expression of synaptic markers and a decrease in growth-associated proteins over the entire culture period. However, morphological analysis of organotypic brain slices cultured from neonatal tissue demonstrated that there were substantial changes to neuronal and glial organization within the neocortex, with a distinct loss of cytoarchitectural stratification and increased GFAP expression (p<0.05). Additionally, cultures from neonatal tissue had no glial limitans and, after 14 DIV, displayed substantial cellular protrusions from slice edges, including cells that expressed both glial and neuronal markers.ConclusionIn summary, we present a substantial evaluation of the viability and morphological changes that occur in the neocortex of whole brain tissue cultures, from different ages, over an extended period of culture.

| S-EPMC3137607 | biostudies-literature

Multiscale Computer Modeling of Spreading Depolarization in Brain Slices.

Project description:Spreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and is associated with several neurologic conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (two voltage-gated ion channels; three leak channels; three ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thicknesses) with ion (K+, Cl-, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+ pumps. SD propagated through the slices at realistic speeds of 2-4 mm/min, which increased by as much as 50% in models incorporating the effects of hypoxia or propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make testable predictions, including the following: (1) SD can be inhibited by enlarging ECS volume; (2) SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; (3) SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; (4) Slice thickness influences SD because of relative hypoxia in the slice core, exacerbated by SD in a pathologic cycle; and (5) SD and high neuronal spike rates will be observed in the core of the slice. Cells in the periphery of the slice near an oxygenated bath will resist SD.

| S-EPMC9410770 | biostudies-literature

Functional Characterization of Three-Dimensional Cortical Cultures for In Vitro Modeling of Brain Networks.

Project description:Three-dimensional (3D) in vitro cultures recapitulate key features of the brain including morphology, cell-cell and cell-extracellular matrix interactions, gradients of factors, and mechanical properties. However, there remains a need for experimental and computational tools to investigate network functions in these 3D models. To address this need, we present an experimental system based on 3D scaffold-based cortical neuron cultures in which we expressed the genetically encoded calcium indicator GCaMP6f to record neuronal activity at the millimeter-scale. Functional neural network descriptors were computed with graph-theory-based network analysis methods, showing the formation of functional networks at 3 weeks of culture. Changes to the functional network properties upon perturbations to glutamatergic neurotransmission or GABAergic neurotransmission were quantitatively characterized. The results illustrate the applicability of our 3D experimental system for the study of brain network development, function, and disruption in a biomimetic microenvironment.

| S-EPMC7452433 | biostudies-literature

Neuronal metabolism governs cortical network response state.

Project description:The level of arousal in mammals is correlated with metabolic state and specific patterns of cortical neuronal responsivity. In particular, rhythmic transitions between periods of high activity (up phases) and low activity (down phases) vary between wakefulness and deep sleep/anesthesia. Current opinion about changes in cortical response state between sleep and wakefulness is split between neuronal network-mediated mechanisms and neuronal metabolism-related mechanisms. Here, we demonstrate that slow oscillations in network state are a consequence of interactions between both mechanisms. Specifically, recurrent networks of excitatory neurons, whose membrane potential is partly governed by ATP-modulated potassium (K(ATP)) channels, mediate response-state oscillations via the interaction between excitatory network activity involving slow, kainate receptor-mediated events and the resulting activation of ATP-dependent homeostatic mechanisms. These findings suggest that K(ATP) channels function as an interface between neuronal metabolic state and network responsivity in mammalian cortex.

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Sliced Human Cortical Organoids for Modeling Distinct Cortical Neuronal Layer Formation

Project description:Brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture representative of late developmental stages. Here, we establish the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death and sustains neurogenesis in organized neural progenitor zones throughout long-term cultures. This method leads to the formation of an expanded cortical plate that establishes distinct upper and deep cortical layers, resembling the third-trimester human neocortex. Using the SNO system, we further identify a critical role of WNT/β-Catenin signaling in regulating cortical neuron fate specification, which is disrupted by a psychiatric disorder-associated genetic mutation in patient iPSC-derived organoids. These results demonstrate the utility of SNOs as a model for investigating previously inaccessible human-specific late-stage cortical developmental and disease-relevant mechanisms

2020-03-05 | GSE137941 | GEO

Altered Loyalties of Neuronal Markers in Cultured Slices of Resected Human Brain Tissue.

Project description:Organotypic cultures from normal neocortical tissue obtained at epilepsy surgery show a severe injury response. This response involves both neuronal degeneration and the proliferation of reactive cells. A salient feature of the reactive cells is the co-expression of microglial and astrocytic markers. Surprisingly, the reactive cells also began to express neuronal markers Tubulin βIII and MAP2 adding to the confusion about their origin. Concomitant with their appearance in reactive cells MAP2 and Tubulin βIII expression disappeared from neurons. While NeuN expression decreased significantly, it did not entirely disappear from many neurons. Moreover, it was not observed in reactive cells, showing that NeuN is a reliable marker of neurons.

| S-EPMC8029075 | biostudies-literature

Time lapse recording of cortical interneuron migration in mouse organotypic brain slices and explants.

Project description:Interneuron migration involves repetitive cycles of pausing and motion that include nucleokinesis and dynamic branching of the leading process. Here, we provide a step-by-step description of how to culture and record the migration of cortical interneurons. We provide two culture models: the first includes organotypic brain slices and the second medial ganglionic eminence (MGE) explants. While organotypic brain slices provide a close-to-physiological context to analyze interneuron migration into cortical streams, MGE explants are appropriate to investigate the fine details of interneuron morphology remodeling during movement. For complete details on the use and execution of this protocol, please refer to Silva et al. (2018).

| S-EPMC8082162 | biostudies-literature

Functional Electron Microscopy, "Flash and Freeze," of Identified Cortical Synapses in Acute Brain Slices.

Project description:How structural and functional properties of synapses relate to each other is a fundamental question in neuroscience. Electrophysiology has elucidated mechanisms of synaptic transmission, and electron microscopy (EM) has provided insight into morphological properties of synapses. Here we describe an enhanced method for functional EM ("flash and freeze"), combining optogenetic stimulation with high-pressure freezing. We demonstrate that the improved method can be applied to intact networks in acute brain slices and organotypic slice cultures from mice. As a proof of concept, we probed vesicle pool changes during synaptic transmission at the hippocampal mossy fiber-CA3 pyramidal neuron synapse. Our findings show overlap of the docked vesicle pool and the functionally defined readily releasable pool and provide evidence of fast endocytosis at this synapse. Functional EM with acute slices and slice cultures has the potential to reveal the structural and functional mechanisms of transmission in intact, genetically perturbed, and disease-affected synapses.

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Structural Brain Network Disturbances in the Psychosis Spectrum.

Project description:BackgroundIndividuals with subclinical psychotic symptoms provide a unique window on the pathophysiology of psychotic experiences as these individuals are free of confounders such as hospitalization, negative and cognitive symptoms and medication use. Brain network disturbances of white matter connections are thought to play a central role in the pathophysiology of psychosis. Based on the structural network disconnection hypothesis in schizophrenia, we expect less and weaker connections, and altered brain network organization in individuals with clinical and those with subclinical psychotic symptoms.MethodsWe used diffusion tensor imaging to study 35 patients with a psychotic disorder, 35 subjects with subclinical psychotic symptoms, and 36 healthy controls. The structural brain network was analyzed on 3 levels: connection density, white matter microstructure (fractional anisotropy, mean diffusivity, and magnetic transfer ratio), and network organization. Network organization was studied with minimum spanning tree analysis, a method to reconstruct a backbone of structural highways in the brain.ResultsDecreased fractional anisotropy and increased mean diffusivity was found in both groups with psychotic symptoms, while their network topology showed decreased overlap with a healthy reference network. Decreased centrality was found in several brain regions, including parietal hubs and language areas, in both groups with psychotic symptoms. Deviation of network characteristics was more apparent in clinical subjects than in subclinical subjects.DiscussionWeaker connections and decreased centrality of parietal hubs characterize the structural brain network in subjects with psychotic symptoms. These differences are more notable in clinical than in subclinical subjects with psychotic experiences.

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Euchromatin histone methyltransferase 1 regulates cortical neuronal network development.

Project description:Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome.

| S-EPMC5073331 | biostudies-other

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