Structure and function of axo-axonic inhibition

Abstract

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

Public Volume Electron Microscopy Data: An Essential Resource to Study the Brain Microvasculature

“…An initial study examined a region of adult mouse visual cortex spanning a volume of 250 × 140 × 90 µm in cortical layers 2/3 ( Schneider-Mizell et al, 2021 ). All parenchymal cell types were segmented in this data set (neurons, astrocytes, microglia) and the vascular wall was segmented as a combined element of both mural cells and endothelial cells.…”

“…Initial data sets, such as the C. elegans data captured in the 1980s ( White et al, 1986 ), were of smaller size due to challenges in imaging, segmentation and data processing. However, recent collaborative efforts through the Machine Intelligence from Cortical networks (MICrONS) consortium ( Dorkenwald et al, 2019 ; Consortium Microns et al, 2021 ; Schneider-Mizell et al, 2021 ) and independent laboratories ( Lee et al, 2016 ; Dorkenwald et al, 2017 ; Bloss et al, 2018 ; Shapson-Coe et al, 2021 ) have generated enormous data sets encompassing up to a cubic millimeter of tissue volume. These publicly available 3D-EM data sets hold immense information on the fine-structure of cerebral microvasculature across different zones of the vascular network, allowing deep exploration of cellular composition, morphology and subcellular interaction between neurovascular cell types.…”

Public volume electron microscopy data: An essential resource to study the brain microvasculature

“…MICrONS Layer 2/3. An initial study examined a region of adult mouse visual cortex spanning a volume of 250 x 140 x 90 µm in cortical layers 2/3 (Schneider-Mizell et al, 2021). All parenchymal cell types were segmented in this data set (neurons, astrocytes, microglia) and the vascular wall was segmented as a combined element of both mural cells and endothelial cells.…”

“…Initial data sets, such as the C. elegans data captured in the 1980s (White et al, 1986), were of smaller size due to challenges in imaging, segmentation and data processing. However, recent collaborative efforts through the Machine Intelligence from Cortical networks (MICrONS) consortium (Dorkenwald et al, 2019;Consortium et al, 2021;Schneider-Mizell et al, 2021) and independent laboratories (Lee et al, 2016;Dorkenwald et al, 2017;Bloss et al, 2018;Shapson-Coe et al, 2021) have generated enormous data sets encompassing up to a cubic millimeter of tissue volume. These publicly available 3D-EM data sets hold immense information on the fine-structure of cerebral microvasculature across different zones of the vascular network, allowing deep exploration of cellular composition, morphology and subcellular interaction between neurovascular cell types.…”

CHRNA5links chandelier cells to severity of amyloid pathology in aging and Alzheimer’s Disease

“…They differ anatomically from the PVALB+ basket cells by their large number of vertically oriented axonal cartridges, which specifically innervate the axon initial segments of pyramidal neurons (Fairén & Valverde, 1980; Somogyi, 1977). New evidence suggests a powerful role of the chandelier cells in regulating excitation dynamics of neuronal networks (Schneider-Mizell et al, 2021). The chandelier cells have been proposed to be involved in diseases involving pathological excitation in the cortex.…”