Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter

Schroeter, Sally; Apparsundaram, Subbu; Wiley, Ronald G.; Miner, Leeann H.; Sesack, Susan R.; Blakely, Randy D.

doi:10.1002/(sici)1096-9861(20000501)420:2<211::aid-cne5>3.0.co;2-3

Cited by 222 publications

(101 citation statements)

References 108 publications

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“…The remainder of the DβH-immunoreactive axon terminals identified that contacted DGL-α-containing dendrites could not be unequivocally classified as asymmetric or symmetric and were classified as undefined. This is consistent with the known morphological features of monoaminergic axon terminals in the FC (Schroeter et al, 2000; Miner et al, 2003; Miner et al, 2006; Farb et al, 2010). …”

Section: Resultssupporting

confidence: 90%

“…Although the present results show that majority of the NET and DβH-immunoreactive axon terminals do not form classically defined synaptic contacts, a finding that is in agreement with previous electron microscopic studies (Schroeter et al, 2000; Miner et al 2003; Miner et al 2006; Farb et al 2010), our results show a slightly higher percentage of synapses formed by NET- and DβH-immunoreactive axon terminals with DGL-α -immunoreactive dendrites compared to previous reports on synapses formed by NE afferents in the FC (Miner et al, 2003; Miner et al, 2006; Farb et al, 2010). Previously, 24% (37/157: Miner et al, 2003) and 18% (130/736: Miner et al, 2006) of NET-immunoreactive terminals and 18% (75/410) of DβH-immunoreactive axon terminals (Farb et al, 2010) form synapses in the prelimbic area of the prefrontal cortex.…”

Section: Discussionsupporting

confidence: 92%

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Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons

2015

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Endocannabinoids (eCBs) are involved in a myriad of physiological processes that are mediated through the activation of cannabinoid receptors, which are ubiquitously distributed within the nervous system. One neurochemical target at which cannabinoids interact to have global effects on behavior is brain noradrenergic circuitry. We, and others, have previously shown that CB type 1 receptors (CB1r) are positioned to pre-synaptically modulate norepinephrine (NE) release in the rat frontal cortex (FC). Diacylglycerol lipase (DGL) is a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). While DGL-α is expressed in the FC in the rat brain, it is not known whether noradrenergic afferents target neurons expressing synthesizing enzymes for the endocannabinoid, 2-AG. In the present study, we employed high-resolution neuroanatomical approaches to better define cellular sites for interactions between noradrenergic afferents and FC neurons expressing DGL-α. Immunofluorescence microscopy showed close appositions between processes containing the norepinephrine transporter (NET) or dopamine-β-hydroxylase (DβH) and cortical neurons expressing DGL-α-immunoreactivity. Ultrastructural analysis using immunogold-silver labeling for DGL-α and immunoperoxidase labeling for NET or DβH confirmed that NET-labeled axon terminals were directly apposed to FC somata and dendritic processes that exhibited DGL-α-immunoreactivity. Finally, tissue sections were processed for immunohistochemical detection of DGL-α , CB1r and DβH. Triple label immunofluorescence revealed that CB1r and DβH were co-localized in common cellular profiles and these were in close association with DGL-α. Taken together, these data provide anatomical evidence for direct synaptic associations between noradrenergic afferents and cortical neurons exhibiting endocannabinoid synthesizing machinery.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 92%

Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons

2015

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“…Neuroanatomical characterization revealed robust transgene expression in the A4 and A6 subdivisions of the LC (Figures 1A–1C), where EGFP/RPL10A perfectly co-localized with the LC-specific NE-synthesizing protein, DßH (Figure 1D), along with reasonably robust co-labeling in the A5 and A7 groups. EGFP/RPL10A labeling was weak and sparse in more caudal DßH+ populations (e.g., A1 and A2), consistent with prior immunofluorescence studies of SLC6A2 expression (Schroeter et al, 2000). Little EGFP expression was seen in ependymal cells, except rarely in cells caudal to the fourth ventricle (data not shown), in contrast to previously reported ependymal expression of SLC6A2.…”

Section: Resultssupporting

confidence: 85%

Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

et al. 2018

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SUMMARY Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females—which we leverage to illustrate the behavioral and pharmacologic relevance of these findings—and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.

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“…Axonal varicosities, rather than synaptic terminals serve as the major release and reuptake sites of neurotransmitter in LC axons. Prior research has shown that varicosities contain NE and the proteins associated with transmitter release and reuptake (Schroeter et al, 2000; Descarries et al, 1977; Chiti and Teschemacher, 2007). Additionally, the monoaminergic system primarily operates via non-synaptic appositions (Beaudet and Descarries, 1978; Agnati et al, 1995; Zoli and Agnati, 1996; Aoki et al, 998; Zoli et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex

Agster

Mejías-Aponte

Clark

et al. 2013

J of Comparative Neurology

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The brainstem nucleus locus coeruleus (LC) is the sole source of norepinephrine (NE)-containing fibers in the mammalian cortex. Previous studies suggest that the density of noradrenergic fibers in rat is relatively uniform across cortical regions and that cells in the nucleus discharge en masse. This implies that activation of the LC results in equivalent release of NE throughout the cortex. However, it is possible that there could be differences in the density of axonal varicosities across regions, and that these differences, rather than a difference in fiber density may contribute to the regulation of NE efflux. Quantification of dopamine beta hydroxylase (DβH) immunostained varicosities was performed on several cortical regions and in the ventral posterior medial (VPM) thalamus using unbiased sampling methods. The density of DβH varicosites is greater in the prefrontal cortex than in motor, somatosensory, or piriform cortices, greater in superficial than in deep layers of cortex, and greater in VPM than in somatosensory cortex. Our results provide anatomical evidence for non-uniform release of NE across functionally discrete cortical regions. This morphology may account for differential, region specific, impact of LC output on different cortical areas.

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Immunolocalization of the cocaine- and antidepressant-sensitive l-norepinephrine transporter

Cited by 222 publications

References 108 publications

Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons

Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons

Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex

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