Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice.
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.
Ferguson
Shawn M
SM
Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37232, USA.
Bazalakova
Mihaela
M
Savchenko
Valentina
V
Tapia
Juan Carlos
JC
Wright
Jane
J
Blakely
Randy D
RD
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D018678:Cholinergic Agents / Q000494:pharmacology; D006426:Hemicholinium 3 / Q000494:pharmacology*; D066298:In Vitro Techniques; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D009435:Synaptic Transmission / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D018678:Cholinergic Agents; D026901:Membrane Transport Proteins; C065637:choline transporter; D006426:Hemicholinium 3; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine