Astrocytes, neurons, synapses: a tripartite view on cortical circuit development

Abstract

In the mammalian cerebral cortex neurons are arranged in specific layers and form connections both within the cortex and with other brain regions, thus forming a complex mesh of specialized synaptic connections comprising distinct circuits. The correct establishment of these connections during development is crucial for the proper function of the brain. Astrocytes, a major type of glial cell, are important regulators of synapse formation and function during development. While neurogenesis precedes astrogenesis in the cortex, neuronal synapses only begin to form after astrocytes have been generated, concurrent with neuronal branching and process elaboration. Here we provide a combined overview of the developmental processes of synapse and circuit formation in the rodent cortex, emphasizing the timeline of both neuronal and astrocytic development and maturation. We further discuss the role of astrocytes at the synapse, focusing on astrocyte-synapse contact and the role of synapse-related proteins in promoting formation of distinct cortical circuits.

Keywords: Astrocyte; Cortex; Development; Neuron; Synapse.

Fig. 1

Overview of the cortex. a Schematic of the rodent brain section in sagittal orientation. Cerebral cortex is shaded in blue. Dashed boxes represent functional cortical areas as labeled. b P7 mouse visual cortex labeled with DAPI (white) to mark cell nuclei. c Same image as b, showing astrocyte marker Aldh1l1 (white), obtained from mice expressing GFP under the Aldh1l1 promoter. Cortical neurons are arranged in 6 layers, marked in red. Astrocytes are present in all cortical layers in the visual cortex. Scale bar = 50 μm

Fig. 2

A combined overview of astrocyte, neuron and synapse generation and development. Timeline (grey) of key developmental processes in the rodent cortex from embryonic stages to the end of the first month of life, from neurogenesis, to astrogenesis to synapse formation, maturation and stabilization. Developmental processes as occur in astrocytes (red, above), and neurons (purple, below) are shown. Each process is represented as a colored bar, with the gradient of color intensity marking the beginning, peak, and end of the process

Fig. 3

Neuronal and astrocytic process elaboration follows a similar timeline as synapse development. a Representative 3-D rendering of layer V rat SSC neurons reconstructed from biocytin-labeled neurons at different ages as labeled (dendrites in red, axons in blue). At P14, 21 and 36 the axons are shown cropped due to space limitations. Scale bar = 200 μm. Adapted with permission from [131]. b Representative images of Lucifer yellow filled rat hippocampal astrocytes at different developmental stages as indicated in each panel. Astrocyte process ramification increases with age. Scale bars = 5 μm. Adapted with permission from [67]. c Development of synapses in the mouse visual cortex visualized by electron microscopy at the different developmental ages as labeled. At P0 neurotransmitter vesicles can be visualized, but the postsynaptic density is not present. At P7, P21 and P30 presynaptic terminals with neurotransmitter vesicles apposed to postsynaptic density structures, marking synaptic contacts, are shown. Asterisk at P30 indicates immunoreactivity for the presynaptic marker synaptophysin. Scale bar = 130 nm. Adapted with permission from [84]

Fig. 4

Timeline of expression of neuronal and astrocytic synapse-related proteins in the cortex [, , , , , , –, –, –, , –136]