Chandelier Cells in Functional and Dysfunctional Neural Circuits

Abstract

Chandelier cells (ChCs; also called axo-axonic cells) are a specialized GABAergic interneuron subtype that selectively innervates pyramidal neurons at the axon initial segment (AIS), the site of action potential generation. ChC connectivity allows for powerful yet precise modulation of large populations of pyramidal cells, suggesting ChCs have a critical role in brain functions. Dysfunctions in ChC connectivity are associated with brain disorders such as epilepsy and schizophrenia; however, whether this is causative, contributory or compensatory is not known. A likely stumbling block toward mechanistic discoveries and uncovering potential therapeutic targets is the apparent lack of rudimentary understanding of ChCs. For example, whether cortical ChCs are inhibitory or excitatory remains unresolved, and thus whether altered ChC activity results in altered inhibition or excitation is not clear. Recent studies have shed some light onto this excitation-inhibition controversy. In addition, new findings have identified preferential cell-type connectivities established by cortical ChCs, greatly expanding our understanding of the role of ChCs in the cortical microcircuit. Here we aim to bring more attention to ChC connectivity to better understand its role in neural circuits, address whether ChCs are inhibitory or excitatory in light of recent findings and discuss ChC dysfunctions in brain disorders.

Keywords: axo-axonic cells; chandelier cells; circuits; epilepsy; interneuron; schizophrenia.

Figure 1

ChCs have unique axonal morphology and innervate pyramidal neurons at the axon initial segment (AIS). Drawing of a ChC (purple) and a connected pyramidal neuron (gray) to illustrate the “chandelier” morphology and the axo-axonic connectivity of ChCs. Arrow indicates the ChC connectivity site at the pyramidal neuron AIS.

Figure 2

Connectivity of cortical ChCs. Simplified schematic of some of the known connections between L2/3 ChCs and other neurons in the cortex. Arrows at terminals indicate excitation; circles at terminals indicate inhibition. Starred and boxed region and insert highlights the ChC synaptic contact with L2/3 pyramidal neurons in which the GABAergic response is not clear. AIS, axon initial segment; BC, basket cell; ChC, chandelier cell; IN, interneuron of unknown subtype; MC, Martinotti cell; NGC, neurogliaform cell; PN, pyramidal neuron; SBC, single-bouquet cell.