Summary
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope, and elevated norepinephrine spillover. Some POTS patients experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE) transporter (NET, SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a critical role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors consistent with reported comorbidities. Mice carrying one A457P allele (NET+/P) exhibited reduced brain and sympathetic NE transport levels compared to wild-type (NET+/+) mice, whereas transport activity in mice carrying two A457P alleles (NETP/P) was nearly abolished. NET+/P and NETP/P mice exhibited elevations in plasma and urine NE levels, reduced DHPG, and reduced DHPG/NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET+/P mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET+/P mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
- Received February 27, 2013.
- Accepted April 3, 2013.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.
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