Specific and Plastic:Chandelier Cell‑to‑Axon Initial Segment Connections in Shaping Functional Cortical Network

Axon initial segment(AIS)is the most excitable subcellular domain of a neuron for action potential initiation.AISs of cortical projection neurons(PNs)receive GABAergic synaptic inputs primarily from chandelier cells(ChCs),which are believed to regulate action potential generation and modulate neuronal excitability.As individual ChCs often innervate hundreds of PNs,they may alter the activity of PN ensembles and even impact the entire neural network.During postnatal development or in response to changes in network activity,the AISs and axo-axonic synapses undergo dynamic structural and functional changes that underlie the wiring,refinement,and adaptation of cortical microcircuits.Here we briefly introduce the history of ChCs and review recent research advances employing modern genetic and molecular tools.Special attention will be attributed to the plasticity of the AIS and the ChC-PN connections,which play a pivotal role in shaping the dynamic network under both physiological and pathological conditions.

Bi-directional Control of Synaptic Input Summation and Spike Generation by GABAergic Inputs at the Axon Initial Segment

Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolarizing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved.Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs,we quantitatively demonstrate that the onset-timing of AIS-GABAergic input,relative to dendritic excitatory glutamatergic inputs,determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC.More specifically,AIS-GABAergic inputs promote the boosting effect of voltage-activated Na+channels on summed synaptic excitation when they precede glutamatergic inputs by>15 ms,while for nearly concurrent excitatory inputs,they primarily produce a shunting inhibition at the AIS.Thus,our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.

Projection-Specific Heterogeneity of the Axon Initial Segment of Pyramidal Neurons in the Prelimbic Cortex

The axon initial segment(AIS)is a highly specialized axonal compartment where the action potential is initiated.The heterogeneity of AISs has been suggested to occur between interneurons and pyramidal neurons(PyNs),which likely contributes to their unique spiking properties.However,whether the various characteristics of AISs can be linked to specific PyN subtypes remains unknown.Here,we report that in the prelimbic cortex(PL)of the mouse,two types of PyNs with axon projections either to the contralateral PL or to the ipsilateral basal lateral amygdala,possess distinct AIS properties reflected by morphology,ion channel expression,action potential initiation,and axo-axonic synaptic inputs from chandelier cells.Furthermore,projection-specific AIS diversity is more prominent in the superficial layer than in the deep layer.Thus,our study reveals the cortical layer-and axon projection-specific heterogeneity of PyN AISs,which may endow the spiking of various PyN types with exquisite modulation.