Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice.

Ferguson SM, Bazalakova M, Savchenko V, Tapia JC, Wright J, Blakely RD
Proc Natl Acad Sci U S A. 2004 101 (23): 8762-7

PMID: 15173594 · PMCID: PMC423269 · DOI:10.1073/pnas.0401667101

Presynaptic acetylcholine (ACh) synthesis and release is thought to be sustained by a hemicholinium-3-sensitive choline transporter (CHT). We disrupted the murine CHT gene and examined CHT-/- and +/- animals for evidence of impaired cholinergic neurotransmission. Although morphologically normal at birth, CHT-/- mice become immobile, breathe irregularly, appear cyanotic, and die within an hour. Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are specifically lost in CHT-/- mouse brains. Moreover, we observe a time-dependent loss of spontaneous and evoked responses at CHT-/- neuromuscular junctions. Consistent with deficits in synaptic ACh availability, we also observe developmental alterations in neuromuscular junction morphology reminiscent of changes in mutants lacking ACh synthesis. Adult CHT+/- mice overcome reductions in CHT protein levels and sustain choline uptake activity at wild-type levels through posttranslational mechanisms. Our results demonstrate that CHT is an essential and regulated presynaptic component of cholinergic signaling and indicate that CHT warrants consideration as a candidate gene for disorders characterized by cholinergic hypofunction.

MeSH Terms (15)

Acetylcholine Animals Brain Choline O-Acetyltransferase Cholinergic Agents Hemicholinium 3 In Vitro Techniques Membrane Transport Proteins Mice Mice, Knockout Motor Neurons Neuromuscular Junction Phenotype Synaptic Transmission Synaptosomes

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