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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An increase of inhibition drives the developmental decorrelation of neural activity

eLife, Год журнала: 2022, Номер 11

Опубликована: Авг. 17, 2022

Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet mechanisms underlying this process are poorly understood. The developmental transition has important functional consequences, as latter is thought allow for more efficient storage, retrieval, processing of information. Here, we show that, in mouse medial prefrontal cortex (mPFC), during first two postnatal weeks decorrelates following specific spatial patterns. This accompanied by concomitant tilting excitation-inhibition (E-I) ratio toward inhibition. Using optogenetic manipulations network modeling, that phenomena mechanistically linked, relative increase inhibition drives decorrelation activity. Accordingly, mice mimicking etiology neurodevelopmental disorders, subtle alterations E-I associated impairments correlational structure spike trains. Finally, capitalizing on EEG data newborn babies, an analogous takes place also human brain. Thus, changes control (de)correlation and, these means, its imbalance might contribute pathogenesis disorders.

Язык: Английский

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Somatostatin interneurons control the timing of developmental desynchronization in cortical networks

Neuron, Год журнала: 2024, Номер 112(12), С. 2015 - 2030.e5

Опубликована: Апрель 9, 2024

Synchronous neuronal activity is a hallmark of the developing brain. In mouse cerebral cortex, decorrelates during second week postnatal development, progressively acquiring characteristic sparse pattern underlying integration sensory information. The maturation inhibition seems critical for this process, but interneurons involved in crucial transition network cortex remain unknown. Using vivo longitudinal two-photon calcium imaging period that precedes change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) as modulators switch mice. Modulation SST+ cells accelerates or delays decorrelation cortical process involves regulating parvalbumin-expressing (PV+) interneurons. critically link inputs with local circuits, controlling neural dynamics while modulating other into nascent circuits.

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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How development sculpts hippocampal circuits and function

Physiological Reviews, Год журнала: 2021, Номер 102(1), С. 343 - 378

Опубликована: Июль 19, 2021

In mammals, the selective transformation of transient experience into stored memory occurs in hippocampus, which develops representations specific events context they occur. this review, we focus on development hippocampal circuits and self-organized dynamics embedded within them since latter critically support role hippocampus learning memory. We first discuss evidence that adult cells are sculpted by as early during embryonic neurogenesis. argue these primary developmental programs provide a scaffold onto later external world can be grafted. Next, review different sequences at anatomical functional levels. cover period extending from neurogenesis migration to appearance phenotypic diversity their wiring networks. describe progressive emergence network sensorimotor-driven sharp waves place tracking relational information. outline critical turn points discontinuities journey, close formulating open questions. propose rewinding process helps understand main organization principles circuits.

Язык: Английский

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Regulation of circuit organization and function through inhibitory synaptic plasticity

Trends in Neurosciences, Год журнала: 2022, Номер 45(12), С. 884 - 898

Опубликована: Окт. 28, 2022

Язык: Английский

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CNS pharmacology of NKCC1 inhibitors

Neuropharmacology, Год журнала: 2021, Номер 205, С. 108910 - 108910

Опубликована: Дек. 6, 2021

The Na-K-2Cl cotransporter NKCC1 and the neuron-specific K-Cl KCC2 are considered attractive CNS drug targets because altered neuronal chloride regulation consequent effects on GABAergic signaling have been implicated in numerous disorders. While modulators not yet clinically available, loop diuretic bumetanide has used clinical studies to treat brain disorders as a tool for inhibition preclinical models. Bumetanide is known anticonvulsant neuroprotective under some pathophysiological conditions. However, shown several species from neonates adults (mice, rats, dogs, by extrapolation humans), at low doses of approved diuresis, this negligible access into CNS, reaching levels that much lower than what needed inhibit cells within parenchyma. Several discovery strategies over last ∼15 years develop brain-permeant compounds that, ideally, should be selective eliminate diuresis mediated renal NKCC2. employed improve pharmacokinetic pharmacodynamic properties blockers include evaluation other diuretics; development lipophilic prodrugs bumetanide; side-chain derivatives unbiased high-throughput screening approaches based large chemical compound libraries. main outcomes (1), non-acidic diuretics such azosemide torasemide may advantages inhibitors vs. (2), achieve significantly higher parent activity; (3), novel do exhibit any functionally relevant improvement accessibility or selectivity (4) discovered resolve inherent problems bumetanide, but achieved. Thus, further research optimize design inhibitors. Another major challenge identify mechanisms whereby various NKCC1-expressing cellular these (e.g., neurons, oligodendrocytes astrocytes) outside parenchyma blood-brain barrier, choroid plexus, endocrine immune system), well molecular off-target effects, might contribute their reported therapeutic adverse effects.

Язык: Английский

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Dysregulation of GABAergic Signaling in Neurodevelomental Disorders: Targeting Cation-Chloride Co-transporters to Re-establish a Proper E/I Balance

Frontiers in Cellular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Янв. 5, 2022

The construction of the brain relies on a series well-defined genetically and experience- or activity -dependent mechanisms which allow to adapt external environment. Disruption these processes leads neurological psychiatric disorders, in many cases are manifest already early postnatal life. GABA, main inhibitory neurotransmitter adult is one major players assembly formation neuronal circuits. In prenatal immediate period acting GABA A receptors, depolarizes excites targeted cells via an outwardly directed flux chloride. this way it activates NMDA receptors voltage-dependent calcium channels contributing, through intracellular rise, shape establish, new synapses elimination others, direction -mediated neurotransmission (depolarizing hyperpolarizing) depends levels chloride [Cl − ] i , turn maintained by cation-chloride importer exporter KCC2 NKCC1, respectively. Thus, premature hyperpolarizing action its persistent depolarizing effect beyond period, behavioral deficits associated with morphological alterations excitatory (E)/inhibitory (I) imbalance selective areas. aim review summarize recent data concerning functional role GABAergic transmission building up refining circuits development dysfunction neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), schizophrenia epilepsy. particular, we focus novel information co-transporters (CCC) generate cognitive impairment diseases. We discuss also possibility re-establish proper balance within areas CCC.

Язык: Английский

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Network state transitions during cortical development

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(8), С. 535 - 552

Опубликована: Май 23, 2024

Язык: Английский

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NKCC1, an Elusive Molecular Target in Brain Development: Making Sense of the Existing Data

Cells, Год журнала: 2020, Номер 9(12), С. 2607 - 2607

Опубликована: Дек. 4, 2020

Ionotropic GABA transmission is mediated by anion (mainly Cl−)-permeable GABAA receptors (GABAARs). In immature neurons, exerts depolarizing and sometimes functionally excitatory actions, based on active uptake of Cl− the Na-K-2Cl cotransporter NKCC1. While functional evidence firmly shows NKCC1-mediated ion transport in diseased molecular detection NKCC1 brain has turned out to be extremely difficult. this review, we describe highly inconsistent data that are available cell type-specific expression patterns mRNA protein CNS. We discuss major technical caveats, including a lack knock-out-controlled immunohistochemistry forebrain, possible effects alternative splicing binding antibodies RNA probes, wide different types, which make whole-tissue analyses useless for studying its neuronal expression. also review novel single-cell RNAseq showing most adult CNS may, fact, expressed non-neuronal cells, especially glia. As future directions, suggest use genetically tagged endogenous proteins or systematically designed antibodies, together with proper knock-out controls, visualization distinct types their subcellular compartments.

Язык: Английский

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