Orchestration of Ion Channels and Transporters in Neocortical Development and Neurological Disorders

Bandô, Yoshio; Ishibashi, Masaru; Yamagishi, Satoru; Fukuda, Atsuo; Sato, Kohji

doi:10.3389/fnins.2022.827284

Cited by 7 publications

(5 citation statements)

References 107 publications

(138 reference statements)

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“…Identifying these mechanism(s) is a first step toward exploring potential cause-and-effect relationships between Syngap1 expression, neuronal IME set points, control of dendritic morphogenesis, and how putative regulation of neuronal maturation directly contributes to building discrete circuit elements during cortical development. IME regulation is heavily linked to function of ion channels that regulate resting membrane potential and membrane resistance (Bando et al, 2022; Smith and Walsh, 2020). We first recorded passive plasma membrane properties from L2/3 SSC neurons within ex vivo slices taken from Syngap1 +/+ and Syngap1 +/- mice shortly after birth (PND1).…”

Section: Resultsmentioning

confidence: 99%

Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Arora

Michaelson

Aceti

et al. 2022

Preprint

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Gene expression intersects with neural activity to produce cortical circuits during brain development. However, the cell biological mechanisms linking gene expression to activity-dependent cortical circuit assembly remain unclear. Here, we demonstrate in mice that a newly discovered function of the neurodevelopmental disorder gene, Syngap1, is to cell-autonomously control intrinsic membrane excitability (IME) in developing cortical glutamatergic neurons. Syngap1 regulation of IME was mechanistically linked to wiring of a cortical circuit motif required for sensory processing and behavioral action. Restoring depressed IME in Syngap1 deficient neurons through genetic targeting of hyper-functional potassium currents unleashed deficient dendritic morphogenesis in upper lamina sensory cortex pyramidal neurons. Furthermore, enhancing dendritic morphogenesis was sufficient to stimulate assembly of translaminar feed-forward excitatory circuit motifs. Thus, Syngap1 promotes excitatory circuit assembly during cortical development by maintaining IME in a range that enables trophic neuronal activity to maximize pyramidal cell somatodendritic maturation and subsequent synapse formation.

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Section: Resultsmentioning

confidence: 99%

Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Arora

Michaelson

Aceti

et al. 2022

Preprint

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“…Neural activity shapes neural development and ongoing plasticity. Electrical stimulation is transduced into a complex cascade of responses ranging from neurotransmitter release to gene transcription, axonal growth, and other functions that depend, to varying degrees, on the movement of numerous molecules along the cytoskeletal network ( 1 ). It is therefore not surprising that Huntingtin (HTT)—a scaffolding protein essential for intracellular transport ( 2 )—is crucial not only for healthy neurophysiology ( 3 – 5 ) but also for neurodevelopment in both mice and humans ( 6 , 7 ).…”

mentioning

confidence: 99%

Treating early postnatal circuit defect delays Huntington’s disease onset and pathology in mice

Braz

Wennagel

Ratié

et al. 2022

Science

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Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington’s disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.

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“…The classical Hodgkin–Huxley model, proposed in 1952, gave perspectives on understanding the electrical properties of neuronal dynamics considering the biophysical mechanics of the exchange of charges by sodium and potassium ion channels [ 1 , 2 ]. Nowadays, much more is known about the variety of channels involved in the neuronal machinery [ 3 , 4 ] and their relation to healthy brain function [ 5 , 6 ] and diseases [ 7 , 8 ]. Despite that, the complete understanding of the role of such ion channels is still inciting many research questions in this matter [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

The Roles of Potassium and Calcium Currents in the Bistable Firing Transition

Borges,

Protachevicz,

Souza

et al. 2023

Brain Sciences

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Healthy brains display a wide range of firing patterns, from synchronized oscillations during slow-wave sleep to desynchronized firing during movement. These physiological activities coexist with periods of pathological hyperactivity in the epileptic brain, where neurons can fire in synchronized bursts. Most cortical neurons are pyramidal regular spiking (RS) cells with frequency adaptation and do not exhibit bursts in current-clamp experiments (in vitro). In this work, we investigate the transition mechanism of spike-to-burst patterns due to slow potassium and calcium currents, considering a conductance-based model of a cortical RS cell. The joint influence of potassium and calcium ion channels on high synchronous patterns is investigated for different synaptic couplings (gsyn) and external current inputs (I). Our results suggest that slow potassium currents play an important role in the emergence of high-synchronous activities, as well as in the spike-to-burst firing pattern transitions. This transition is related to the bistable dynamics of the neuronal network, where physiological asynchronous states coexist with pathological burst synchronization. The hysteresis curve of the coefficient of variation of the inter-spike interval demonstrates that a burst can be initiated by firing states with neuronal synchronization. Furthermore, we notice that high-threshold (IL) and low-threshold (IT) ion channels play a role in increasing and decreasing the parameter conditions (gsyn and I) in which bistable dynamics occur, respectively. For high values of IL conductance, a synchronous burst appears when neurons are weakly coupled and receive more external input. On the other hand, when the conductance IT increases, higher coupling and lower I are necessary to produce burst synchronization. In light of our results, we suggest that channel subtype-specific pharmacological interactions can be useful to induce transitions from pathological high bursting states to healthy states.

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Orchestration of Ion Channels and Transporters in Neocortical Development and Neurological Disorders

Cited by 7 publications

References 107 publications

Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Treating early postnatal circuit defect delays Huntington’s disease onset and pathology in mice

The Roles of Potassium and Calcium Currents in the Bistable Firing Transition

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