Inhibitory Synapse Formation at the Axon Initial Segment

Abstract

The axon initial segment (AIS) is the site of action potential (AP) initiation in most neurons and is thus a critical site in the regulation of neuronal excitability. Normal function within the discrete AIS compartment requires intricate molecular machinery to ensure the proper concentration and organization of voltage-gated and ligand-gated ion channels; in humans, dysfunction at the AIS due to channel mutations is commonly associated with epileptic disorders. In this review, we will examine the molecular mechanisms underlying the formation of the only synapses found at the AIS: synapses containing γ-aminobutyric type A receptors (GABAARs). GABAARs are heteropentamers assembled from 19 possible subunits and are the primary mediators of fast synaptic inhibition in the brain. Although the total GABAAR population is incredibly heterogeneous, only one specific GABAAR subtype—the α2-containing receptor—is enriched at the AIS. These AIS synapses are innervated by GABAergic chandelier cells, and this inhibitory signaling is thought to contribute to the tight control of AP firing. Here, we will summarize the progress made in understanding the regulation of GABAAR synapse formation, concentrating on post-translational modifications of subunits and on interactions with intracellular proteins. We will then discuss subtype-specific synapse formation, with a focus on synapses found at the AIS, and how these synapses influence neuronal excitation.

Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

“…Furthermore, subcellular localization of GABA A Rs also profoundly determines the type of neuronal inhibition exhibited and how GABA A R-targeting drugs will modulate neuronal activity ( Kerti-Szigeti and Nusser, 2016 ; Nathanson et al, 2019 ; Kramer et al, 2020 ). The mobility and diffusion of GABA A Rs between synaptic and extrasynaptic regions are dependent on subunit composition, specific motifs within the intracellular domain of certain subunits, and the interaction of GABA A Rs with scaffolding partners such as gephyrin or radixin ( Jacob et al, 2005 ; Thomas et al, 2005 ; Loebrich et al, 2006 ; Bannai et al, 2009 ; Mukherjee et al, 2011 ; Tyagarajan and Fritschy, 2014 ; Hausrat et al, 2015 ; Hannan et al, 2019 ; Davenport et al, 2020 ).…”

Pathophysiological Roles of Abnormal Axon Initial Segments in Neurodevelopmental Disorders

“…To the best of our knowledge, the only neurotransmission at the AIS through ligandgated ion channels uses γ-aminobutyric acid type A receptors (GABAARs) [50]. GABAARs containing α2 subunits (α2-GABAARs) are specifically enriched in the AIS ( [50]).…”

“…To the best of our knowledge, the only neurotransmission at the AIS through ligandgated ion channels uses γ-aminobutyric acid type A receptors (GABAARs) [50]. GABAARs containing α2 subunits (α2-GABAARs) are specifically enriched in the AIS ( [50]). The AISes of the pyramidal cells of the forebrain contain inhibitory synapses that are exclusively innervated by chandelier cells (ChCs) [51,52].…”

Glycinergic axonal inhibition subserves acute spatial sensitivity to sudden increases in sound intensity

“…A key component of the neuron doctrine is the unidirectional propagation of action potentials, formulated as the ‘law of dynamic polarization’ by Cajal and van Gehuchten ( Berlucchi, 1999 ; Shepherd, 1991 ). As the site where action potentials are typically initiated, the axon initial segment (AIS) has a pivotal role in this process ( Bender and Trussell, 2012 ; Kole and Brette, 2018 ; Leterrier, 2018 ) and is a bottleneck where inhibition can have an ‘outsized’ effect on a neuron’s output, as proposed for chandelier and basket cells ( Blot and Barbour, 2014 ; Nathanson et al, 2019 ). Disruption of such synapses is associated with severe brain disorders ( Wang et al, 2016 ), but their exact functional role in the normal brain is speculative because physiological studies of these synapses have been limited to in vitro recordings.…”