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

AUTOR(ES)

Ferguson, Shawn M.

FONTE

National Academy of Sciences

RESUMO

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.

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