Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior

The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficienc...

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Bibliographic Details
Published in:	Genes, brain and behavior Vol. 12; no. 8; pp. 749 - 759
Main Authors:	Fentress, H. M., Klar, R., Krueger, J. J., Sabb, T., Redmon, S. N., Wallace, N. M., Shirey‐Rice, J. K., Hahn, M. K.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-11-2013 Blackwell John Wiley & Sons, Inc
Subjects:	Adult and adolescent clinical studies Animals Anxiety Anxiety - genetics Anxiety - metabolism Biological and medical sciences Cell Membrane Permeability Cerebral Cortex - metabolism Cerebral Cortex - physiology Depression Dopamine Plasma Membrane Transport Proteins - metabolism genetic heterozygote Hippocampus - metabolism Hippocampus - physiology knockout light–dark box Male Maze Learning Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Miscellaneous Mood disorders Morris water maze norepinephrine Norepinephrine Plasma Membrane Transport Proteins - genetics Norepinephrine Plasma Membrane Transport Proteins - metabolism Organic Cation Transport Proteins - metabolism Proteins Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Rodents Serotonin Plasma Membrane Transport Proteins - metabolism Synaptosomes - metabolism tail suspension transporter Affect affectivity Morris water maze light―dark box Biological transport Cognition Space perception heterozygote Acquisition process tail suspension Light Illumination Genetics Anxiety Behavior Mood disorder genetic knockout Depressions Depression Suspension Catecholamine Heterozygosity Animal Knockout mouse transporter Null mutation Norepinephrine Perceptive learning norepinephrine light-dark box depression
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Summary:	The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface‐resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing surface NET proteins. The NET+/− mice exhibit increased anxiety in the open field and light–dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. The NET+/− mice compensate for a deficit in NET plasma membrane expression with normal NE transport activity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1601-1848 1601-183X
DOI:	10.1111/gbb.12084