Review

Transient cortical circuits match spontaneous and sensory-driven activity during development

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Science  16 Oct 2020:
Vol. 370, Issue 6514, eabb2153
DOI: 10.1126/science.abb2153

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A moment in time

As the brain develops, it does not simply get bigger. Like a building that depends on temporary scaffolds as its structures are assembled, the developing brain sets up the circuits that characterize the adult brain. Molnár et al. review the current state of knowledge about how brain connections are built and how autonomously established patterns are reshaped by activity from the sensory periphery. With the help of a transient population of neurons, the spontaneous activity of early circuits is molded by increasing inputs from the external world. When these normal developmental interactions are disrupted, consequent miswiring drives dysfunction in the adult brain.

Science, this issue p. eabb2153

Structured Abstract

BACKGROUND

During early mammalian brain development, transient neurons and circuits form the scaffold for the development of neuronal networks. In the immature cerebral cortex, subplate neurons in the lower cortical layer and Cajal-Retzius cells in the marginal zone lay the foundations for cortical organization in horizontal layers and translaminar radial circuits (“cortical columns”). Patterns of spontaneous activity during early development synchronize local and large-scale cortical networks, which form the functional template for generation of cortical architecture and guide establishment of global thalamocortical and intracortical networks. These networks become established in an autonomous fashion before the arrival of signals from the sensory periphery and before the maturation of cortical circuits. The subplate, which is a transient structure located below the developing cortical plate, orchestrates alignment of these autonomously established pathways by integrating spontaneous and sensory-driven activity patterns during critical stages of early development.

ADVANCES

The subplate contains heterogeneous neuronal populations with distinct characteristics, such as origin, birthdate, neurotransmitters, receptor expression, morphology, projections, firing properties, and their participation in specific intra- and extracortical connectivity. The transformation of this early subplate-driven circuit to the adult-like cortex requires patterned spontaneous activity and depends on the awakening of silent synapses in the cortical plate when thalamic inputs are progressively integrated. Moreover, a subpopulation of the glutamatergic and GABAergic (GABA, γ-aminobutyric acid) subplate neurons has widespread axonal projections that establish early large-scale networks. The early circuits are remodeled when Cajal-Retzius and subplate neurons largely disappear by programmed cell death. Both the programmed cell death and the remodeling of circuits may be also controlled by the transition from spontaneous synchronized burst to sensory-driven activity.

OUTLOOK

Functional impairments of these transient circuits (that include both transient and more permanent cell types) have great clinical relevance. Genetic abnormalities or early pathological conditions such as in utero infection, inflammation, exposure to pharmacological compounds, or hypoxia-ischemia induce functional disturbances in early microcircuits, which may lead to cortical miswiring at later stages and subsequent neurological and psychiatric conditions. A better understanding of the transition from early transient to permanent neuronal circuits will clarify mechanisms driving abnormal distribution and persistence of subplate neurons as interstitial white matter cells in pathophysiological conditions. Exploring the transition from transient to permanent circuits helps us to understand causal foundations of certain pharmaco-resistant epilepsies and psychiatric conditions and to consider new therapeutic strategies to treat such disorders.

Early spontaneous synchronized neuronal activity sculpts cortical architecture.

(A) Schematic outlines of brain development from the embryonic stage to adult. (B and C) Prenatal cortical circuits are dominated by early-generated, largely transient neurons in the subplate (SP) and marginal zone (MZ) before maturation of cortical plate (CP) neurons. (D to H) Transformation of early subplate-driven circuits to the adult-like six-layered cortex requires spontaneous synchronized burst activity (D) that also controls programmed cell death (apoptosis), arrangement of neurites and axons, and formation and awakening of synapses. Most subplate neurons disappear with development; a few survive in rodents as layer (L) 6b neurons or in primates as interstitial white matter (WM) cells (G). During prenatal and early postnatal stages, pathophysiological conditions such as hypoxia-ischemia, drugs, infection or inflammation may alter spontaneous activity [(E) and (F)]. These altered activity patterns may disturb subsequent developmental programs, including apoptosis (H). Surviving subplate neurons that persist in white matter or L6b may support altered circuits that could cause neurological or psychiatric disorders.

Abstract

At the earliest developmental stages, spontaneous activity synchronizes local and large-scale cortical networks. These networks form the functional template for the establishment of global thalamocortical networks and cortical architecture. The earliest connections are established autonomously. However, activity from the sensory periphery reshapes these circuits as soon as afferents reach the cortex. The early-generated, largely transient neurons of the subplate play a key role in integrating spontaneous and sensory-driven activity. Early pathological conditions—such as hypoxia, inflammation, or exposure to pharmacological compounds—alter spontaneous activity patterns, which subsequently induce disturbances in cortical network activity. This cortical dysfunction may lead to local and global miswiring and, at later stages, can be associated with neurological and psychiatric conditions.

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