Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD

Culotta, Lorenza; Penzes, Peter

doi:10.1186/s13229-020-00339-0

Cited by 45 publications

(39 citation statements)

References 135 publications

(154 reference statements)

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“…Millions of chronic disease patients with organ insufficiency that cannot be treated with transplant or pharmacotherapy rely on the possibility that 1 day personalized-specific iPS cells might integrate in target tissues and become a routine in regenerative medicine. In terms of brain function, this type of approach is being used to treat ischemia to replenish neural cells and to approach autism spectral disorder as many proteins involved in the regulation of synaptic plasticity, neuronal excitability, and neuronal connectivity are inappropriately developmentally generated or misplaced, disturbing the neuronal network activity ( Culotta and Penzes, 2020 ). On Alzheimer’s disease, early hyperexcitability is linked to widespread synapse loss and cognitive dysfunction, and therefore a culture model derived from human cerebral organoids might shed some light on a synaptic plasticity model comparing aberrant neural networks from controls ( Ghatak et al, 2020 ).…”

Section: Neural Cell Lineages Derived From Ips Cellsmentioning

confidence: 99%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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Complex dynamic cellular networks have been studied in physiological and pathological processes under the light of single-cell calcium imaging (SCCI), a method that correlates functional data based on calcium shifts operated by different intracellular and extracellular mechanisms integrated with their cell phenotypes. From the classic synaptic structure to tripartite astrocytic model or the recent quadripartite microglia added ensemble, as well as other physiological tissues, it is possible to follow how cells signal spatiotemporally to cellular patterns. This methodology has been used broadly due to the universal properties of calcium as a second messenger. In general, at least two types of receptor operate through calcium permeation: a fast-acting ionotropic receptor channel and a slow-activating metabotropic receptor, added to exchangers/transporters/pumps and intracellular Ca 2+ release activated by messengers. These prototypes have gained an enormous amount of information in dynamic signaling circuits. SCCI has also been used as a method to associate phenotypic markers during development and stage transitions in progenitors, stem, vascular cells, neuro- and glioblasts, neurons, astrocytes, oligodendrocytes, and microglia that operate through ion channels, transporters, and receptors. Also, cancer cells or inducible cell lines from human organoids characterized by transition stages are currently being used to model diseases or reconfigure healthy cells in terms of the expression of calcium-binding/permeable molecules and shed light on therapy.

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Section: Neural Cell Lineages Derived From Ips Cellsmentioning

confidence: 99%

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

2020

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“…Although there is a number of etiological hypotheses, one of the most researched etiological mechanisms in the development of ASD in the last decade is the E/I imbalance in key cortical and subcortical neuronal circuits ( 75 , 89 , 90 ). This hypothesis was first proposed in the seminal work of Rubenstein and Merzenich in 2003 ( 74 ).…”

Section: Discussionmentioning

confidence: 99%

Electroencephalography in Assessment of Autism Spectrum Disorders: A Review

Milovanović

Grujičić

2021

Front. Psychiatry

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Electroencephalography (EEG) can further out our understanding of autistic spectrum disorders (ASD) neurophysiology. Epilepsy and ASD comorbidity range between 5 and 46%, but its temporal relationship, causal mechanisms and interplay with intellectual disability are still unknown. Epileptiform discharges with or without seizures go as high as 60%, and associate with epileptic encephalopathies, conceptual term suggesting that epileptic activity can lead to cognitive and behavioral impairment beyond the underlying pathology. Seizures and ASD may be the result of similar mechanisms, such as abnormalities in GABAergic fibers or GABA receptor function. Epilepsy and ASD are caused by a number of genetic disorders and variations that induce such dysregulation. Similarly, initial epilepsy may influence synaptic plasticity and cortical connection, predisposing a growing brain to cognitive delays and behavioral abnormalities. The quantitative EEG techniques could be a useful tool in detecting and possibly measuring dysfunctions in specific brain regions and neuronal regulation in ASD. Power spectra analysis reveals a U-shaped pattern of power abnormalities, with excess power in the low and high frequency bands. These might be the consequence of a complicated network of neurochemical changes affecting the inhibitory GABAergic interneurons and their regulation of excitatory activity in pyramidal cells. EEG coherence studies of functional connectivity found general local over-connectivity and long-range under-connectivity between different brain areas. GABAergic interneuron growth and connections are presumably impaired in the prefrontal and temporal cortices in ASD, which is important for excitatory/inhibitory balance. Recent advances in quantitative EEG data analysis and well-known epilepsy ASD co-morbidity consistently indicate a role of aberrant GABAergic transmission that has consequences on neuronal organization and connectivity especially in the frontal cortex.

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“…Increased neuron numbers within the PFCx are noted in children with ASD [17]. Moreover, disturbed cortical excitation-inhibition balance is considered to be one of the pathophysiological mechanisms of ASD [60][61][62]. TAOK2 belongs to the MAP kinase kinase kinase (MAP3K) family, which regulates the p38 MAPK, SAPK/JNK and Hippo signaling pathways [63].…”

Section: Discussionmentioning

confidence: 99%

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

Gawlińska

Gawliński

Kowal-Wiśniewska

et al. 2021

IJMS

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Epidemiological and preclinical studies suggest that maternal obesity increases the risk of autism spectrum disorder (ASD) in offspring. Here, we assessed the effects of exposure to modified maternal diets limited to pregnancy and lactation on brain development and behavior in rat offspring of both sexes. Among the studied diets, a maternal high-fat diet (HFD) disturbed the expression of ASD-related genes (Cacna1d, Nlgn3, and Shank1) and proteins (SHANK1 and TAOK2) in the prefrontal cortex of male offspring during adolescence. In addition, a maternal high-fat diet induced epigenetic changes by increasing cortical global DNA methylation and the expression of miR-423 and miR-494. As well as the molecular changes, behavioral studies have shown male-specific disturbances in social interaction and an increase in repetitive behavior during adolescence. Most of the observed changes disappeared in adulthood. In conclusion, we demonstrated the contribution of a maternal HFD to the predisposition to an ASD-like phenotype in male adolescent offspring, while a protective effect occurred in females.

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Exploring the mechanisms underlying excitation/inhibition imbalance in human iPSC-derived models of ASD

Cited by 45 publications

References 135 publications

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

Electroencephalography in Assessment of Autism Spectrum Disorders: A Review

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

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