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• α-Syn is expressed predominantly in cholinergic nerve varicosities and terminals in the mouse colon. • α-Syn KO mice had a higher enteric neuron density and a larger proportion of cholinergic neurons. • α-Syn deletion enhanced the amplitude of nicotinic receptor-mediated [Ca2+] i transients in the ENS. Alpha-Synuclein (α-Syn) is expressed in the central nervous system and the nervous system of the gut (enteric nervous system, ENS), and is well known to be the major constituent of Lewy bodies which are the hallmark of Parkinson's disease. Gastrointestinal disorders frequently manifest several years before motor deficits develop in Parkinson's patients. Despite extensive research on pathological rodent models, the physiological role of α-Syn in the normal ENS is unclear hampering analysis of its neuropathology. We compared the ENS in colons of α-Syn-knockout (α-Syn KO) and wild-type mice using immunohistochemistry and calcium-imaging of responses to synaptic input. We found that α-Syn is predominantly expressed in cholinergic varicosities, which contain vesicular acetylcholine transporter. α-Syn KO mice had higher enteric neuron density and a larger proportion of cholinergic neurons, notably those containing calretinin, demonstrating a role for α-Syn in regulating development of these neurons. Moreover, α-Syn deletion enhanced the amplitude of synaptically activated [Ca2+] i transients that are primarily mediated by acetylcholine activating nicotinic receptors suggesting that α-Syn modulates the availability of acetylcholine in enteric nerve terminals. [ABSTRACT FROM AUTHOR]