Comprehensive Genetic Targeting Reveals Brain-Wide Distribution and Synaptic Input Patterns of GABAergic Axo-Axonic Interneurons

Core Concepts

Axo-axonic interneurons, also known as chandelier cells, are widely distributed across the mouse brain and receive distinct patterns of synaptic inputs in different brain regions.

Abstract

The authors used an intersectional genetic strategy to comprehensively target axo-axonic interneurons (AACs) across the mouse brain. They discovered that AACs are present in essentially all pallium-derived brain structures, including the neocortex, hippocampus, claustrum-insular complex, extended amygdala, and olfactory centers.

In the neocortex, the authors quantified the areal, laminar, and morphological diversity of AACs. They found that AACs exhibit characteristic laminar distribution patterns, with the majority occupying a narrow band just below the layer 1/2 border, and a smaller proportion forming a second band above the white matter. Sparse labeling revealed multiple AAC subtypes, including supragranular, infragranular, and translaminar types.

In the hippocampus, AACs were most abundant in CA2, with sparser populations in CA1, CA3, and dentate gyrus. In the amygdala and olfactory centers, AACs exhibited more multipolar morphologies compared to the laminar patterns observed in the cortex and hippocampus.

The authors further used an intersectional viral tracing approach to map the long-range synaptic inputs to AACs in sensorimotor cortical areas and the CA1 region of the hippocampus. AACs received inputs from diverse sources, including motor, sensory, and other cortical areas, as well as thalamic and subcortical regions. The input patterns differed between AACs and parvalbumin-expressing interneurons, suggesting distinct functional roles.

Overall, this study provides a comprehensive mapping of AACs across the mouse brain and reveals their diverse distribution, morphological subtypes, and synaptic connectivity, setting the stage for understanding their role in circuit development and function.

Stats

The density of AACs is approximately 3-4 fold higher in CA2 compared to CA1 and CA3, and 13-fold higher than in the dentate gyrus.
The density of AACs in the dorsal endopiriform nucleus is about 5-fold higher than in the ventral endopiriform nucleus.
AACs in sensorimotor cortical areas receive around 50% of their long-range inputs from motor areas, 20-60% from sensory areas, and the remaining from other cortical and subcortical regions.

Quotes

"AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers."
"The comprehensive labeling of cortical AACs allowed us to quantify their areal, laminar, and axon terminal distribution as well as to describe multiple anatomic subtypes."
"AACs received inputs from diverse sources, including motor, sensory, and other cortical areas, as well as thalamic and subcortical regions. The input patterns differed between AACs and parvalbumin-expressing interneurons, suggesting distinct functional roles."

Key Insights Distilled From

Specific and comprehensive genetic targeting reveals brain-wide distribution and synaptic input patterns of GABAergic axo-axonic interneurons

by Raudales,R.,... at www.biorxiv.org 11-08-2023

https://www.biorxiv.org/content/10.1101/2023.11.07.566059v2

Deeper Inquiries

What are the developmental origins and genetic programs that give rise to the diverse distribution and subtypes of axo-axonic interneurons across the brain

Axo-axonic interneurons, also known as AACs or chandelier cells, have diverse distribution and subtypes across the brain due to their distinct developmental origins and genetic programs. These interneurons originate from the medial ganglionic eminence (MGE) during embryonic development. The MGE is a subpallial structure that gives rise to a variety of GABAergic interneurons in the telencephalon. Within the MGE lineage, AACs are generated in two consecutive waves during both early and late neurogenesis. The expression of specific transcription factors, such as Nkx2.1, plays a crucial role in defining the identity of MGE interneurons, including AACs. Additionally, molecular markers like Unc5b and Pthlh have been identified as potential markers for targeting AACs in specific brain regions. By combining lineage origin markers with molecular markers, researchers have been able to achieve specific and comprehensive targeting of AACs throughout the brain, revealing their distribution in various pallium-derived structures and beyond.

How do the distinct synaptic input patterns of axo-axonic interneurons in different brain regions contribute to their functional roles in regulating neural circuit dynamics and information processing

The distinct synaptic input patterns of axo-axonic interneurons in different brain regions play a crucial role in their functional roles in regulating neural circuit dynamics and information processing. AACs are known for their selective innervation of glutamatergic projection neurons at their axon initial segments (AIS), allowing them to exert precise control over the spiking activity of these neurons. The synaptic inputs to AACs come from a variety of sources, including local and long-range connections. In the cerebral cortex, AACs receive inputs from both excitatory and inhibitory neurons, allowing them to modulate the activity of pyramidal neurons and regulate network operations. In the hippocampus, AACs receive inputs from regions such as the medial septum, contributing to the coordination of network oscillations and the generation of sharp waves. The specific patterns of synaptic inputs to AACs in different brain regions enable them to play a critical role in the synchronization of neural activity, the generation of rhythmic oscillations, and the integration of information across brain circuits.

Given the broad distribution of axo-axonic interneurons, how might their dysfunction or dysregulation contribute to neurological and psychiatric disorders affecting multiple brain systems

The dysfunction or dysregulation of axo-axonic interneurons, with their broad distribution across multiple brain systems, can have significant implications for neurological and psychiatric disorders. Given their role in regulating neural circuit dynamics and information processing, alterations in the activity or connectivity of AACs can disrupt the balance between excitation and inhibition in the brain. This imbalance has been implicated in various disorders, including epilepsy, schizophrenia, and autism spectrum disorders. In epilepsy, dysfunction of AACs can lead to hyperexcitability and seizure activity due to the loss of their inhibitory control over pyramidal neurons. In schizophrenia, abnormalities in AAC function may contribute to cognitive deficits and altered sensory processing. Additionally, disruptions in the synaptic input patterns to AACs from different brain regions can impact the overall network activity and information flow, leading to cognitive and behavioral impairments. Understanding the role of AAC dysfunction in these disorders is essential for developing targeted therapeutic interventions to restore normal brain function.