Cardiovascular and Neuropsychiatric Consequences of a Genetic Loss of the High-Affinity Choline Transporter (CHT)

Abstract

Acetylcholine (ACh) was one of the first neurotransmitters discovered and has been implicated in regulating a number of physiologic processes within the CNS and the periphery. Cholinergically-mediated physiology requires continuous turnover of ACh by the biosynthesis machinery to maintain cholinergic tone. High-affinity choline uptake (HACU), mediated by CHT in cholinergic terminals is pivotal for efficient ACh production and release. Cardiovascular function relies on a balanced integration of noradrenergic and cholinergic innervation of the heart. The cardiovascular impact of diminished CHT expression has not been directly examined, due to the transporter’s inaccessibility in vivo. We describe findings from cardiovascular studies using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (-/-) exhibit early postnatal lethality, heterozygous (CHT+/-) mice survive, exhibiting normal spontaneous behaviors. However, the CHT+/- mouse heart displays significantly reduced levels of HACU, accompanied by reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice reveal basal tachycardia and hypertension. After treadmill exercise, CHT+/- mice exhibit slower heart rate recovery, consistent with diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Functional studies revealed an age-dependent decrease in fractional shortening and increased ventricular fibrosis, consistent with progressive ventricular dysfunction. Lastly, we show that the hypomorphic allele (Ile89Val) in human CHT is associated with overall symptom severity in patients with major depressive disorder (MDD) and was shown to be selectively overtransmitted in the combined subtype of attention-deficit hyperactivity disorder (ADHD). The identification of cardiovascular phenotypes in mice with deficits in CHT may provide potential biomarkers for the identification of autonomic dysfunction in a number of cardiovascular and neuropsychiatric disorders. Autonomic dysfunction has been indentified in a number of neuropsychiatric disorders contributing to morbidity and mortality. The increased allele frequency and selective transmission of the hypomorphic CHT allele in patients with psychiatric disorders demonstrates the importance of CHT not only in regulating CNS processes, but in regulating autonomic processes in patients with these disorders. Further studies examining the role of CHT in regulating autonomic imbalance may provide potential targets for novel therapeutics.