Research Article

Postnatal connectomic development of inhibition in mouse barrel cortex

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Science  29 Jan 2021:
Vol. 371, Issue 6528, eabb4534
DOI: 10.1126/science.abb4534

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Building circuits, one synapse at a time

As the brain develops, neurons build new connections that are refined by pruning. Gour et al. used electron microscopy to build a high-resolution study of mouse postnatal brain development. The survey reveals the details of how circuits are built to incorporate inhibitory neurons in the somatosensory cortex.

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Structured Abstract

INTRODUCTION

The establishment of neuronal circuits in the cerebral cortex of mammals is an important developmental process extending over embryonic and postnatal periods, from the first occurrence of differentiated neurons to the final formation of precise synaptic innervation patterns, which are further shaped by experience. Of special interest is the establishment of inhibitory circuits, constituted by nerve cells that produce γ-aminobutyric acid as a neurotransmitter (GABAergic interneurons), which are known to form intricate neuronal networks with a distinctive degree of synaptic preference for the types of postsynaptic structures to innervate. While the time course of neuronal migration and integration of interneurons is beginning to be understood and the first molecular cues for selectively enhancing and suppressing synaptic innervation have been identified, a comprehensive mapping of cortical inhibitory innervation during postnatal development is missing.

RATIONALE

With the development of high-throughput three-dimensional electron microscopy (3D EM) imaging and analysis of nervous tissue, the goal of systematically mapping neuronal connectivity in ever-increasing volumes of brain tissue has become possible. This methodological approach, connectomics, has so far been primarily aimed at comprehensive circuit mapping in complete smaller animals’ brains or parts of larger brains. An additional advantage of higher-throughput connectomic analysis, however, is the opportunity to repeat similar experiments under many experimental conditions. This advantage is particularly relevant for the study of developmental processes, which naturally require the measurement of multiple time points. In this study, we made use of these technological advances to map neuronal connectivity in 13 3D EM datasets with a focus on the primary somatosensory cortex of mouse during postnatal development.

RESULTS

We acquired and analyzed data from layers 4 and 2/3 of mouse cortex over the period during which synaptic networks are formed within the neocortex. We studied data from mice at 5, 7, 9, 14, 28, and 56 days of age, corresponding to the development from baby to adult. We analyzed the formation of interneuronal synaptic preference for subsections of neurons, their cell bodies, their initial part of the axon, and apical dendrites. We found that only axons with preference for apical dendrites already show high target preference in the early time points measured. By contrast, preference for innervation of cell bodies was gradually established, with a peak in developmental change between postnatal days 7 and 9. During this time, preference for cell bodies increased almost threefold, and the density of synapses along these axons dropped by almost twofold. With this, we found that while for apical dendrite–preferring interneurons, mechanisms of ab initio target choice are plausible, cell body innervation could be established by the removal of inadequately placed synapses along the presynaptic axon. For the innervation of the initial section of axons, we found that axo-axonic innervation initially constitutes only a minor fraction of the innervation and develops to provide ~50% of the synaptic input to the axon initial segment. Our data indicate that synaptic preference for axon initial segments develops before the formation of special vertically oriented axonal configurations called cartridges.

CONCLUSION

The first comprehensive mapping of inhibitory circuit development in mammalian cortex provides quantitative insights into the formation of circuits and the precise time course for the establishment of synaptic target preference. The approach of connectomic screening also may prove useful for future studies of experimental interference with relevant genetic and environmental conditions of circuit formation in the mammalian brain.

Connectomic mapping of inhibitory circuits during postnatal development.

Data from 7, 9, and 14 days of age are shown, with cell bodies, axons, and dendrites reconstructed. Under the datasets, matrices describing the neuronal connectivity (“connectomes”) are displayed. Synaptic preference for cell bodies, dendrites, and axon initial segments is a hallmark of circuit structure in the cerebral cortex, and this connectomic developmental screening study uncovers precise timelines of the synaptic preference development in the cortex.

Abstract

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

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