Axon Initial Segment Plasticity in Affective Disorders

The axon initial segment (AIS) is a highly specialized compartment of the neuron thought to be an essential regulator of how neurons encode their responses. This region is topographically and biophysically tuned to the precise generation of action potentials and the regulation of spiking output. In addition to serving as a threshold region like other axonal regions, the AIS is uniquely optimized as a signaling domain so that cytoskeletal polarization, ion channel clustering, and intracellular signaling pathways converge upon this subcellular domain to produce a precise regulation of neuronal firing rate and timing. The nanoscale cytoskeletons and anchoring scaffolds at the AIS serve both to confine and to dynamically mobilize key signaling proteins and channels for a rapid yet adaptable regulation of spike initiation. Evidence suggests that AIS structure is exquisitely plastic to cellular, environmental, immune, and genetic factors known to be involved in the neuropathology of mood disorders. Precursors to pathology such as stress, chronic glucocorticoid excess, neural inflammatory signals, and genetic variation perturbing excitability by governing ion channel and receptor expression, can all produce alterations in the positional or dimensional parameters of the AIS with functional consequence to neuronal gain. Such alterations occur specifically in circuit nodes of emotion regulation such as the prefrontal limbic circuit, across neuronal populations and cell types, and alter trajectories of circuit function seemingly aligned with affective disorder symptom states. This work integrates current knowledge in the structure and electrophysiology of AIS function, activity dependent plasticity, and psychiatric neuroscience, to develop the hypothesis that remodeling of the AIS represents a convergent readout of the interactions between the immune system, stress response, and genetic alleles on neuronal function, a cellular mechanism through which the large components of neural circuit-based disease shape affective illness, potentially as an “axonopathy”. Furthermore, this review highlights the AIS as a potential new therapeutic target aimed at rehabilitating excitability threshold and gain for effective circuit function in the treatment of affective disorders within the emerging paradigm of precision psychiatry.