The postnatal GABA shift: A developmental perspective

Neuroscience & Biobehavioral Reviews, Год журнала: 2021, Номер 124, С. 179 - 192

Опубликована: Фев. 4, 2021

GABA is the major inhibitory neurotransmitter that counterbalances excitation in mature brain. The action of relies on inflow chloride ions (Cl-), which hyperpolarizes neuron. In early development, signaling induces outward Cl- currents and depolarizing. postnatal shift from depolarizing to hyperpolarizing a pivotal event brain development its timing affects function throughout life. Altered associated with several neurodevelopmental disorders. Here, we argue represents final sequence shifts, regulating proliferation, migration, differentiation, finally plasticity developing neurons. Each developmental ensures instructive role matches circumstances network. Sensory input may be crucial factor determining proper shift. A perspective necessary interpret full consequences mismatch between connectivity, activity during development.

Язык: Английский

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Keeping Your Brain in Balance: Homeostatic Regulation of Network Function

Annual Review of Neuroscience, Год журнала: 2024, Номер 47(1), С. 41 - 61

Опубликована: Фев. 21, 2024

To perform computations with the efficiency necessary for animal survival, neocortical microcircuits must be capable of reconfiguring in response to experience, while carefully regulating excitatory and inhibitory connectivity maintain stable function. This dynamic fine-tuning is accomplished through a rich array cellular homeostatic plasticity mechanisms that stabilize important network features such as firing rates, information flow, sensory tuning properties. Further, these functional properties can stabilized by different forms plasticity, including target or synapses, regulate intrinsic neuronal excitability. Here we discuss which aspects circuit function are under control, how this homeostasis realized on molecular levels, pathological consequences when impaired. A remaining challenge elucidate diverse cooperate within complex circuits enable them both flexible stable.

Язык: Английский

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Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior

Neuron, Год журнала: 2021, Номер 109(23), С. 3838 - 3850.e8

Опубликована: Окт. 14, 2021

The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the "chandelier" or axo-axonic (AACs). Although AACs are only cellular source GABA targeting segment, their in vivo activity patterns and influence over cell dynamics not well understood. We achieved cell-type-specific genetic access to mice show that area CA1 synchronously activated episodes locomotion whisking during rest. Bidirectional intervention experiments head-restrained performing random foraging task revealed inhibit cells, indicating effect on segments hippocampus inhibitory vivo. Finally, optogenetic inhibition at specific track locations induced remapping place fields. These results demonstrate brain-state-specific critical controller cortical circuits.

Язык: Английский

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Structure and function of axo-axonic inhibition

eLife, Год журнала: 2021, Номер 10

Опубликована: Дек. 1, 2021

Inhibitory neurons in mammalian cortex exhibit diverse physiological, morphological, molecular, and connectivity signatures. While considerable work has measured the average of several interneuron classes, there remains a fundamental lack understanding distribution distinct inhibitory cell types with synaptic resolution, how it relates to properties target cells, affects function. Here, we used large-scale electron microscopy functional imaging address these questions for chandelier cells layer 2/3 mouse visual cortex. With dense reconstructions from microscopy, mapped complete input onto 153 pyramidal neurons. We found that synapse number is highly variable across population correlated structural features neuron. This variability axo-axonic ChC synapses higher than seen perisomatic inhibition. Biophysical simulations show observed pattern inhibition particularly effective controlling excitatory output when excitation are co-active. Finally, activity awake animals using cell-type-specific calcium approach saw cells. In same experiments, vivo pupil dilation, proxy arousal. Together, results suggest provide circuit-wide signal whose strength adjusted relative

Язык: Английский

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Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Янв. 4, 2021

Abstract The axon initial segment (AIS) is a critical microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent plasticity. While structural AIS plasticity has been suggested to fine-tune activity when network states change, whether it acts vivo as homeostatic regulatory mechanism behaviorally relevant contexts remains poorly understood. Using mouse whisker-to-barrel pathway model system combination with immunofluorescence, confocal analysis electrophysiological recordings, we observed bidirectional cortical pyramidal neurons. Furthermore, find that functional remodeling occurs distinct temporal domains: Long-term sensory deprivation elicits an length increase, accompanied increase excitability, while enrichment results rapid shortening, by decrease generation. Our findings highlight central role input-output relations.

Язык: Английский

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The Multifaceted Roles of KCC2 in Cortical Development

Trends in Neurosciences, Год журнала: 2021, Номер 44(5), С. 378 - 392

Опубликована: Фев. 24, 2021

KCC2, best known as the neuron-specific chloride-extruder that sets strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule can regulate cytoskeletal dynamics via its C-terminal domain (CTD). We describe molecular cellular mechanisms involved in multiple functions KCC2 splice variants, ranging from developmental apoptosis control early network events to formation plasticity cortical dendritic spines. The versatility actions at subcellular levels also evident mature neurons plasticity, disease, aging. Thus, has emerged one most important molecules shape overall phenotype.

Язык: Английский

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Postnatal connectomic development of inhibition in mouse barrel cortex

Science, Год журнала: 2020, Номер 371(6528)

Опубликована: Дек. 3, 2020

Brain circuits in the neocortex develop from diverse types of neurons that migrate and form synapses. Here we quantify circuit patterns synaptogenesis for inhibitory interneurons developing mouse somatosensory cortex. We studied synaptic innervation cell bodies, apical dendrites, axon initial segments using three-dimensional electron microscopy focusing on first 4 weeks postnatally (postnatal days P5 to P28). found dendrites occurs early specifically: Target preference is already almost at adult levels P5. Axons innervating other hand, gradually acquire specificity P9, likely via overabundance followed by antispecific synapse removal. Chandelier axons show target P14 but full completely P28, which consistent with a combination outgrowth off-target This connectomic developmental profile reveals how cortex establish brain circuitry during development.

Язык: Английский

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Impaired bidirectional communication between interneurons and oligodendrocyte precursor cells affects social cognitive behavior

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Март 16, 2022

Cortical neural circuits are complex but very precise networks of balanced excitation and inhibition. Yet, the molecular cellular mechanisms that form balance just beginning to emerge. Here, using conditional γ-aminobutyric acid receptor B1- deficient mice we identify a acid/tumor necrosis factor superfamily member 12-mediated bidirectional communication pathway between parvalbumin-positive fast spiking interneurons oligodendrocyte precursor cells determines density function in developing medial prefrontal cortex. Interruption GABAergic signaling results reduced myelination hypoactivity interneurons, strong changes cortical network activities impaired social cognitive behavior. In conclusion, glial transmitter receptors pivotal elements finetuning distinct brain functions.

Язык: Английский

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Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony

Cell Reports, Год журнала: 2021, Номер 37(3), С. 109855 - 109855

Опубликована: Окт. 1, 2021

The protein tau has been implicated in many brain disorders. In animal models, reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic behavioral abnormalities various conditions associated with excessive excitation-inhibition (E/I) ratios. However, the underlying mechanisms are unknown. Global genetic ablation mice reduces action potential (AP) firing E/I ratio pyramidal cells acute cortical slices without affecting excitability these cells. Tau excitatory inputs to inhibitory neurons, increases cells, structurally alters their axon initial segments (AISs). primary neuronal cultures subjected prolonged overstimulation, diminishes homeostatic response AISs promotes inhibition, hypersynchrony. Together, differential alterations neurons help explain how prevents network hypersynchrony counteracts disorders causing abnormally increased

Язык: Английский

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Microglia regulate chandelier cell axo-axonic synaptogenesis

Proceedings of the National Academy of Sciences, Год журнала: 2022, Номер 119(11)

Опубликована: Март 9, 2022

SignificanceChandelier cells (ChCs) are a unique type of GABAergic interneuron that form axo-axonic synapses exclusively on the axon initial segment (AIS) neocortical pyramidal neurons (PyNs), allowing them to exert powerful yet precise control over PyN firing and population output. The importance proper ChC function is further underscored by association connectivity defects with various neurological conditions. Despite this, cellular mechanisms governing synapse formation remain poorly understood. Here, we identify microglia as key regulators axonal morphogenesis AIS synaptogenesis, show disease-induced aberrant microglial activation perturbs synaptic development/connectivity in neocortex. In doing so, such findings highlight therapeutic potential manipulating ensure brain wiring.

Язык: Английский

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