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

Molecular Autism, Journal Year: 2020, Volume and Issue: 11(1)

Published: May 11, 2020

Abstract Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders characterized by impaired social interaction and communication, repetitive or restricted behaviors. ASD subjects exhibit complex genetic clinical heterogeneity, thus hindering the discovery pathophysiological mechanisms. Considering that several ASD-risk genes encode proteins involved in regulation synaptic plasticity, neuronal excitability, connectivity, one hypothesis has emerged arises from disruption network activity due to perturbation excitation inhibition (E/I) balance. The development induced pluripotent stem cell (iPSC) technology recent advances differentiation techniques provide unique opportunity model connectivity test E/I human-based models. Here, we aim review latest studying different cellular molecular mechanisms contributing balance using iPSC-based vitro models ASD.

Language: Английский

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Direction selectivity in retinal bipolar cell axon terminals

Neuron, Journal Year: 2021, Volume and Issue: 109(18), P. 2928 - 2942.e8

Published: Aug. 13, 2021

The ability to encode the direction of image motion is fundamental our sense vision. Direction selectivity along four cardinal directions thought originate in direction-selective ganglion cells (DSGCs) because directionally tuned GABAergic suppression by starburst cells. Here, utilizing two-photon glutamate imaging measure synaptic release, we reveal that all arises earlier than expected at bipolar cell outputs. Individual contained distinct populations axon terminal boutons with different preferred directions. We further show this bouton-specific tuning relies on cholinergic excitation from and inhibition wide-field amacrine DSGCs received both aligned inputs untuned among heterogeneously glutamatergic bouton populations. Thus, directional excitatory visual pathway incrementally refined terminals their recipient DSGC dendrites two neurotransmitters co-released

Language: Английский

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Hierarchical retinal computations rely on hybrid chemical-electrical signaling

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112030 - 112030

Published: Jan. 25, 2023

Bipolar cells (BCs) are integral to the retinal circuits that extract diverse features from visual environment. They bridge photoreceptors ganglion cells, source of output. Understanding how such encode requires an accounting mechanisms control glutamate release bipolar cell axons. Here, we demonstrate orientation selectivity in a specific genetically identifiable type mouse cell-type 5A (BC5A). Their synaptic terminals respond best when stimulated with vertical bars far larger than their dendritic fields. We provide evidence this involves enhanced excitation for stimuli gap junctional coupling through connexin36. also show is detectable postsynaptically direction-selective which were not previously thought be selective orientation. Together, these results multiple extracted by single hierarchical network, engaging distinct electrical and chemical pathways.

Language: Английский

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A circuit suppressing retinal drive to the optokinetic system during fast image motion

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 23, 2023

Optokinetic nystagmus (OKN) assists stabilization of the retinal image during head rotation. OKN is driven by ON direction selective ganglion cells (ON DSGCs), which encode both and speed global slip. The synaptic circuits responsible for selectivity DSGCs are well understood, but those sculpting their slow-speed preference remain enigmatic. Here, we probe this mechanism in mouse retina through patch clamp recordings, functional imaging, genetic manipulation, electron microscopic reconstructions. We confirm earlier evidence that feedforward glycinergic inhibition main suppressor DSGC responses to fast motion, reveal source inhibition-the VGluT3 amacrine cell, a dual neurotransmitter, excitatory/inhibitory interneuron. Together, our results identify role limiting range OKN. More broadly, they suggest shape response many cell types suppressing it some while enhancing others.

Language: Английский

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A presynaptic source drives differing levels of surround suppression in two mouse retinal ganglion cell types

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 18, 2024

Abstract In early sensory systems, cell-type diversity generally increases from the periphery into brain, resulting in a greater heterogeneity of responses to same stimuli. Surround suppression is canonical visual computation that begins within retina and found at varying levels across retinal ganglion cell types. Our results show level surround occurs subcellularly bipolar synapses. Using single-cell electrophysiology serial block-face scanning electron microscopy, we two types exhibit very different even though they receive input This divergence signal through synapse-specific regulation by amacrine cells scale tens microns. These findings indicate each synapse single can carry unique signal, expanding number possible functional channels earliest stages processing.

Language: Английский

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Rapid multi-directed cholinergic transmission in the central nervous system

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: March 2, 2021

Abstract In many parts of the central nervous system, including retina, it is unclear whether cholinergic transmission mediated by rapid, point-to-point synaptic mechanisms, or slower, broad-scale ‘non-synaptic’ mechanisms. Here, we characterized ultrastructural features connections between direction-selective starburst amacrine cells and downstream ganglion in an existing serial electron microscopy data set, as well their functional properties using electrophysiology two-photon acetylcholine (ACh) imaging. Correlative results demonstrate that a ‘tripartite’ structure facilitates ‘multi-directed’ form transmission, which ACh released from single vesicle rapidly (~1 ms) co-activates receptors expressed multiple neurons located within ~1 µm release site. Cholinergic signals are at local, but not global scale, facilitate transfer information to cell dendrites. These suggest distinct operational framework for signaling bears hallmarks non-synaptic forms transmission.

Language: Английский

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Retinal receptive-field substructure: scaffolding for coding and computation

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(6), P. 430 - 445

Published: April 11, 2022

The center-surround receptive field of retinal ganglion cells represents a fundamental concept for how the retina processes and encodes visual information. Yet, traditional approaches using as linear filter to integrate light intensity over space often do not capture responses cell complex stimuli. Thus, models with local nonlinearities in subunits or temporal dynamics are emerging better reflect relevant aspects circuitry stimulus encoding. Here, we review recent efforts identify such receptive-field substructure evaluate its role concomitant development new computational tools may pave way toward model-based, functional approach circuit analysis.

Language: Английский

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Asymmetric Activation of ON and OFF Pathways in the Degenerated Retina

eNeuro, Journal Year: 2024, Volume and Issue: 11(5), P. ENEURO.0110 - 24.2024

Published: May 1, 2024

Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns spiking retinal ganglion cells (RGCs) response electrical stimulation, but less examined underlying circuitry that is activated by stimulation drive these responses. Surprisingly, little known about role inhibition generating responses or how might be altered during Using whole-cell voltage-clamp recordings subretinal rd10 wild-type (wt) retina, we found electrically evoked synaptic inputs differed between ON OFF RGC populations, receiving mostly excitation very excitation. We bipolar limits RGCs, a majority both pre- postsynaptic pathway arises from glycinergic amacrine cells, contributes inhibitory RGC. also show this presynaptic greater compared wt retina.

Language: Английский

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Electrical Compartmentalization in Neurons

Cell Reports, Journal Year: 2019, Volume and Issue: 26(7), P. 1759 - 1773.e7

Published: Feb. 1, 2019

Highlights•Neural computation relies on compartmentalized dendrites to discern inputs•A method is described systematically derive the degree of compartmentalization•There are substantially fewer functional compartments than dendritic branches•Compartmentalization dynamic and can be tuned by synaptic inputsSummaryThe tree neurons plays an important role in information processing brain. While it thought that require independent subunits perform most their computations, still not understood how they compartmentalize into subunits. Here, we show these deduced from properties dendrites. We devised a formalism links arborization impedance-based graph topology this reveals This analysis cooperativity between synapses decreases slowly with increasing electrical separation thus few coexist. nevertheless find balanced inputs or shunting inhibition modify increase number size context-dependent manner. also recompartmentalization enable branch-specific learning stimulus features. Analysis patch-clamp recording experiments confirmed our theoretical predictions.Graphical abstract

Language: Английский

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Asymmetries in the Architecture of ON and OFF Arbors in ON–OFF Direction‐Selective Ganglion Cells

The Journal of Comparative Neurology, Journal Year: 2025, Volume and Issue: 533(1)

Published: Jan. 1, 2025

ABSTRACT Direction selectivity is a fundamental feature in the visual system. In retina, direction independently computed by ON and OFF circuits. However, advantages of extracting directional information from these two independent circuits are unclear. To gain insights, we examined ON–OFF direction‐selective ganglion cells (DSGCs), which recombine signals both Specifically, investigated dendritic architecture neurons with premise that asymmetries will provide insights into function. Scrutinizing dendrites dye‐filled DSGCs reveals arbors substantially denser. The increase density can be primarily attributed to higher branching seen arbors. Further, analysis previously published serial block‐face electron microscopy dataset revealed denser packed more bipolar synapses per unit length. These suggest DSGC preferentially magnifies synaptic drive pathway, potentially allowing it encode distinct pathway.

Language: Английский

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