Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice.

Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (-/-) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/- mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/- mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/- mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity.

The high-affinity choline transporter: a critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice.

In cholinergic neurons, the presynaptic choline transporter (CHT) mediates high-affinity choline uptake (HACU) as the rate-limiting step in acetylcholine (ACh) synthesis. It has previously been shown that HACU is increased by behaviorally and pharmacologically-induced activity of cholinergic neurons in vivo, but the molecular mechanisms of this change in CHT function and regulation have only recently begun to be elucidated. The recent cloning of CHT has led to the generation of new valuable tools, including specific anti-CHT antibodies and a CHT knockout mouse. These new reagents have allowed researchers to investigate the possibility of a presynaptic, CHT-mediated, molecular plasticity mechanism, regulated by and necessary for sustained in vivo cholinergic activity. Studies in various mouse models of cholinergic dysfunction, including acetylcholinesterase (AChE) transgenic and knockout mice, choline acetyltransferase (ChAT) heterozygote mice, muscarinic (mAChR) and nicotinic (mAChR) receptor knockout mice, as well as CHT knockout and heterozygote mice, have revealed new information about the role of CHT expression and regulation in response to long-term alterations in cholinergic neurotransmission. These mouse models highlight the capacity of CHT to provide for functional compensation in states of cholinergic dysfunction. A better understanding of modes of CHT regulation should allow for experimental manipulation of cholinergic signaling in vivo with potential utility in human disorders of known cholinergic dysfunction such as Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, and dysautonomia.