Striatal Cholinergic Signaling in Time and Space

The cholinergic interneurons of the striatum account for a small fraction of all striatal cell types but due to their extensive axonal arborization give the striatum the highest content of acetylcholine of almost any nucleus in the brain. The prevailing theory of striatal cholinergic interneuron signaling is that the numerous varicosities on the axon produce an extrasynaptic, volume-transmitted signal rather than mediating rapid point-to-point synaptic transmission. We review the evidence for this theory and use a mathematical model to integrate the measurements reported in the literature, from which we estimate the temporospatial distribution of acetylcholine after release from a synaptic vesicle and from multiple vesicles during tonic firing and pauses. Our calculations, together with recent data from genetically encoded sensors, indicate that the temporospatial distribution of acetylcholine is both short-range and short-lived, and dominated by diffusion. These considerations suggest that acetylcholine signaling by cholinergic interneurons is consistent with point-to-point transmission within a steep concentration gradient, marked by transient peaks of acetylcholine concentration adjacent to release sites, with potential for faithful transmission of spike timing, both bursts and pauses, to the postsynaptic cell. Release from multiple sites at greater distance contributes to the ambient concentration without interference with the short-range signaling. We indicate several missing pieces of evidence that are needed for a better understanding of the nature of synaptic transmission by the cholinergic interneurons of the striatum.