Axo‐axonic synapses: Diversity in neural circuit function

Abstract

The chemical synapse is the principal form of contact between neurons of the central nervous system. These synapses are typically configured as presynaptic axon terminations onto postsynaptic dendrites or somata, giving rise to axo‐dendritic and axo‐somatic synapses, respectively. Beyond these common synapse configurations are less‐studied, non‐canonical synapse types that are prevalent throughout the brain and significantly contribute to neural circuit function. Among these are the axo‐axonic synapses, which consist of an axon terminating on another axon or axon terminal. Here, we review evidence for axo‐axonic synapse contributions to neural signaling in the mammalian nervous system and survey functional neural circuit motifs enabled by these synapses. We also detail how recent advances in microscopy, transgenics, and biological sensors may be used to identify and functionally assay axo‐axonic synapses.

Molecular self-avoidance in synaptic neurexin complexes

“…Both two dendrites generate pre- and postsynaptic specializations, thereby assembling a two-neuron microcircuit, the smallest possible neural circuit. Similarly, at axo-axonic synapses formed by inhibitory neurons onto presynaptic terminals, an axonal membrane assembles both pre- and postsynaptic specializations ( 11 , 12 ). In these synapses, pre- and postsynaptic specializations are adjacent to each other in the same plasma membrane domain.…”

Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors

“…Dopamine terminals are frequently localized in tight contact with other axons configuring a triad—a configuration in which a neuron is connected to both the pre-synaptic element and post-synaptic (usually dendritic) target. Triads are common in the hippocampus, striatum, and medial frontal cortex (for a review, see [ 124 ]). These triads can contain both dopamine and serotonin or adrenergic terminals.…”

Synaptic Spinules are Reliable Indicators of Excitatory Presynaptic Bouton Size and Strength in CA1 Hippocampus

“…Indeed, these findings raise the possibility that axo-axonic communication may be more common than presently understood. While there are examples of axo-axonic communication across brain regions (Cover and Mathur, 2021), axo-axonic synaptic contacts likely comprise a small minority of the total excitatory and inhibitory synapses across the brain (Somogyi et al, 1982; DeFelipe and Fariñas, 1992; Inan et al, 2013). Thus, if as we’ve shown 45% of CA1 excitatory synapses contain AdjAx spinules (i.e., 74% of presynaptic boutons are SBBs, and 61% of these contain AdjAx spinules), and there are ∼30,000 synapses per pyramidal neuron (Megías et al, 2001), each CA1 pyramidal neuron would have ∼13,500 presynaptic boutons that envelop and putatively communicate (see Potential Functions below) with other axons and boutons.…”