Abstract
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.
Highlights
The cholinergic interneurons of the striatum (CINs) form a local network, specific to the striatum, and distinct from the forebrain cholinergic neurons
CINs account for a small fraction of all striatal cell types [1,2,3], they are a rich source of acetylcholine [4], and together with extrinsic afferents [5] give the striatum a higher content of ACh than any other part of the brain, apart from the interpeduncular nucleus [6]
The higher density of cholinergic synapses versus cholinergic varicosities with synaptic specializations might indicate that a large fraction (e.g., 60%) of cholinergic synapses are on axons rather than varicosities, as is the case in dopamine axons when carefully examined by serial-section electron microscopy [58]
Summary
The cholinergic interneurons of the striatum (CINs) form a local network, specific to the striatum, and distinct from the forebrain cholinergic neurons. The axons have varicosities containing mitochondria and vesicles [2,7,13], some of which form symmetrical synaptic specializations [2,14,15] These findings established the synaptic nature of cholinergic neurotransmission by CINs in the striatum, Descarries et al [16,17] on the basis of a systematic electron microscopic analysis of the varicosities [13], reported that fewer than 10% of those varicosities displayed synaptic membrane specializations. In this review we reexamine quantitative aspects of ACh neurotransmission and, using a simple mathematical model to integrate our findings, estimate how these quantitative details might affect the spatiotemporal dynamics of ACh concentration and signaling by CINs in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
