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

Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8762-7. doi: 10.1073/pnas.0401667101. Epub 2004 Jun 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / physiology*
  • Animals
  • Brain / drug effects
  • Brain / physiology
  • Choline O-Acetyltransferase / metabolism
  • Cholinergic Agents / pharmacology
  • Hemicholinium 3 / pharmacology*
  • In Vitro Techniques
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / physiology
  • Mice
  • Mice, Knockout
  • Motor Neurons / drug effects
  • Motor Neurons / physiology
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / physiology
  • Phenotype
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism

Substances

  • Cholinergic Agents
  • Membrane Transport Proteins
  • choline transporter
  • Hemicholinium 3
  • Choline O-Acetyltransferase
  • Acetylcholine