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

Abstract

Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remains poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage (Nkx2.1) and molecular (Unc5b,Pthlh) markers. We discovered that 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. AACs are also abundant in anterior olfactory nucleus, taenia tecta and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally

“…No capillary endothelial cells were observed, indicating that the intersectional strategy allowed for restricted gene expression in ChCs. These results are consistent with the recent preprint study that has used the same intersectional strategies ( 33 ).…”

“…To assess the impact of direct synaptic input on AIS plasticity, we used an intersectional genetic strategy to label and manipulate ChCs ( 32 , 33 ). To do this, two sets of driver lines are involved ( Fig.…”

Association cortical areas in the mouse contain a large population of fast‐spiking GABAergic neurons that do not express parvalbumin

“…The chandelier cells negative for PV might contribute to the fast-spiking population not expressing PV of association cortices. Indeed, a recent study shows that chandelier cells seem to be very abundant in PrL/IL and in PER/ECT areas, though their PV expression was not tested (Raudales et al, 2023). However, we did not find any electrophysiological difference in between PV-expressing and PV-negative fastspiking neurons in PER, whereas Taniguchi et al (2013) described several differences in the biophysical properties of chandelier cells as compared with PV-expressing basket cells (Taniguchi et al, 2013).…”